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1
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Soleimani Samarkhazan H, Zehtabcheh S, Seraji HR, Beqaj SH, Tayefeh S, Mohammadi MH, Aghaei M. Unveiling the potential of CLL-1: a promising target for AML therapy. Biomark Res 2025; 13:28. [PMID: 39940055 PMCID: PMC11823018 DOI: 10.1186/s40364-025-00738-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/30/2025] [Indexed: 02/14/2025] Open
Abstract
Acute myeloid leukemia (AML) remains a formidable blood cancer, despite recent advances in treatment. A significant challenge persists in improving patient outcomes, particularly in addressing relapse and treatment resistance. Identifying new therapeutic targets is critical for advancing AML therapy. C-type lectin-like molecule-1 (CLL-1) has emerged as a promising therapeutic target in AML. This cell surface receptor is highly expressed on AML blasts and demonstrates stable expression throughout disease progression. CLL-1's consistent presence makes it an ideal candidate for monitoring minimal residual disease (MRD), which is a critical indicator for predicting relapse. Beyond its utility as a diagnostic marker, CLL-1 offers exciting potential in the development of immunotherapies. Emerging strategies, such as CAR-T-cell therapy and antibody-drug conjugates (ADCs), are being investigated to leverage the immune system against CLL-1-expressing AML cells. This review examines the structure, function, and expression patterns of CLL-1 in AML and other hematologic malignancies, providing insights into its role in disease pathogenesis and treatment potential. Exploring CLL-1 as a target for diagnosis, MRD monitoring, and immunotherapy opens new avenues for AML treatment. A deeper understanding of its relationship with AML pathogenesis will aid in the development of targeted therapies, offering hope for improved patient outcomes in the future.
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Affiliation(s)
- Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Zehtabcheh
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamideh Rahmani Seraji
- Department of Hematology and Oncology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shamim Tayefeh
- UCLA Immunogenetics Center, Immunogenetics (UIC), 1000 Veteran Ave, Los Angeles, CA, 90024, USA
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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2
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Luo B, Li W, Zeng J, Mao Y, He S, Hu N, Guo Q, Zheng X. FHL1 as a prognostic biomarker and therapeutic target in acute promyelocytic leukaemia. Discov Oncol 2025; 16:59. [PMID: 39827436 PMCID: PMC11743414 DOI: 10.1007/s12672-025-01738-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 01/01/2025] [Indexed: 01/22/2025] Open
Abstract
Acute myeloid leukemia (AML) has a poor prognosis and high heterogeneity. Most cases of leukemias are caused by environmental factors interacting with the cell's genetic material, but treatment is still dominated by cell cycle drugs. Therefore, there is an urgent need to find reliable biomarkers. Based on the Gene Expression Omnibus database, Kaplan-Meier survival analysis and univariate Cox regression analysis were used to select the genes that had the most significant influence on the prognosis of patients with AML. Quantitative real-time PCR and Western blot were used to assess the effects of small interfering RNA transfection and lentiviral interference on the gene's knockout and overexpression, respectively. These method were also used to confirm the expression levels of the FHL1 gene in the HL60 cell line compared to neutrophils.. Cell Counting Kit-8 and flow cytometry were used to detect the effect of high or low expression of FHL1 on cell viability and apoptosis under the influence of cytarabine and daunorubicin. FHL1 was found to be the most prognostic independent biomarker by GSE12417 screening and GSE37642 validation. FHL1 is highly expressed in AML, and knockdown of FHL1 can increase the sensitivity of AML cells to cytarabine and daunorubicin. FHL1 may play a role as a potential molecular marker and therapeutic target for predicting poor prognosis of AML and for direct treatment (chemotherapy).
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Affiliation(s)
- Bo Luo
- Basic Medical School, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Wei Li
- Enyang District People's Hospital of Bazhong City, Bazhong, 636600, Sichuan, People's Republic of China
| | - Jingyuan Zeng
- School of Nursing, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Yingyu Mao
- Basic Medical School, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Shuang He
- School of Public Health, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Nan Hu
- Basic Medical School, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Qulian Guo
- Department of Pediatrics, Children Hematological Oncology and Birth Defects Laboratory, Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Xiaoli Zheng
- Basic Medical School, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
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3
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Prajapati SK, Kumari N, Bhowmik D, Gupta R. Recent advancements in biomarkers, therapeutics, and associated challenges in acute myeloid leukemia. Ann Hematol 2024; 103:4375-4400. [PMID: 39198271 DOI: 10.1007/s00277-024-05963-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024]
Abstract
Acute myeloid leukemia (AML) is a common type of leukemia that has a high mortality rate. The reasons for high mortality in patients with AML are therapeutic resistance, limited ability to predict duration of response, and likelihood of cancer relapse. Biomarkers, such as leukemic stem cell biomarkers, circulatory biomarkers, measurable residual disease biomarkers, and molecular biomarkers, are used for prognosis, diagnosis, and targeted killing to selectively eliminate AML cells. They also play an indispensable role in providing therapeutic resistance to patients with AML. Therefore, targeting these biomarkers will improve the outcome of AML patients. However, identifying biomarkers that can differentiate between treatment-responsive and non-responsive AML patients remains a challenge. This review discusses recent advancements in AML biomarkers, promising therapeutics, and associated challenges in the treatment of AML.
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Affiliation(s)
- Suresh Kumar Prajapati
- Research and Development Cell, Parul Institute of Applied Sciences, Parul University, Vadodara, 391760, India
| | - Neha Kumari
- Parul Institute of Applied Sciences, Parul University, Vadodara, 380060, India
| | - Doulat Bhowmik
- Parul Institute of Applied Sciences, Parul University, Vadodara, 380060, India
| | - Reeshu Gupta
- Research and Development Cell, Parul Institute of Applied Sciences, Parul University, Vadodara, 391760, India.
- Parul Institute of Applied Sciences, Parul University, Vadodara, 380060, India.
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4
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Bauer K, Hauswirth A, Gleixner KV, Greiner G, Thaler J, Bettelheim P, Filik Y, Koller E, Hoermann G, Staber PB, Sperr WR, Keil F, Valent P. BRD4 degraders may effectively counteract therapeutic resistance of leukemic stem cells in AML and ALL. Am J Hematol 2024; 99:1721-1731. [PMID: 38822666 DOI: 10.1002/ajh.27385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/03/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024]
Abstract
Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are life-threatening hematopoietic malignancies characterized by clonal expansion of leukemic blasts in the bone marrow and peripheral blood. The epigenetic reader BRD4 and its downstream effector MYC have recently been identified as potential drug targets in human AML and ALL. We compared anti-leukemic efficacies of the small-molecule BET inhibitor JQ1 and the recently developed BRD4 degraders dBET1 and dBET6 in AML and ALL cells. JQ1, dBET1, and dBET6 were found to suppress growth and viability in all AML and ALL cell lines examined as well as in primary patient-derived AML and ALL cells, including CD34+/CD38- and CD34+/CD38+ leukemic stem and progenitor cells, independent of the type (variant) of leukemia or molecular driver expressed in leukemic cells. Moreover, we found that dBET6 overcomes osteoblast-induced drug resistance in AML and ALL cells, regardless of the type of leukemia or the drug applied. Most promising cooperative or even synergistic drug combination effects were seen with dBET6 and the FLT3 ITD blocker gilteritinib in FLT3 ITD-mutated AML cells, and with dBET6 and the multi-kinase blocker ponatinib in BCR::ABL1+ ALL cells. Finally, all BRD4-targeting drugs suppressed interferon-gamma- and tumor necrosis factor-alpha-induced expression of the resistance-related checkpoint antigen PD-L1 in AML and ALL cells, including LSC. In all assays examined, the BRD4 degrader dBET6 was a superior anti-leukemic drug compared with dBET1 and JQ1. Together, BRD4 degraders may provide enhanced inhibition of multiple mechanisms of therapy resistance in AML and ALL.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/genetics
- Transcription Factors
- Triazoles/pharmacology
- Triazoles/therapeutic use
- Azepines/pharmacology
- Azepines/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Cell Cycle Proteins/antagonists & inhibitors
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Cell Line, Tumor
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Pyrazines/pharmacology
- Pyrazines/therapeutic use
- Drug Synergism
- Pyridazines/pharmacology
- Pyridazines/therapeutic use
- Bromodomain Containing Proteins
- Aniline Compounds
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Affiliation(s)
- Karin Bauer
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Alexander Hauswirth
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Karoline V Gleixner
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Georg Greiner
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria
| | - Johannes Thaler
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | | | - Yüksel Filik
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Koller
- Third Medical Department for Hematology and Oncology, Hanusch Hospital Vienna, Vienna, Austria
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- MLL Munich Leukemia Laboratory, Munich, Germany
| | - Philipp B Staber
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang R Sperr
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Felix Keil
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Third Medical Department for Hematology and Oncology, Hanusch Hospital Vienna, Vienna, Austria
| | - Peter Valent
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
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5
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Zhou J, Chng WJ. Unveiling novel insights in acute myeloid leukemia through single-cell RNA sequencing. Front Oncol 2024; 14:1365330. [PMID: 38711849 PMCID: PMC11070491 DOI: 10.3389/fonc.2024.1365330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
Acute myeloid leukemia (AML) is a complex and heterogeneous group of aggressive hematopoietic stem cell disease. The presence of diverse and functionally distinct populations of leukemia cells within the same patient's bone marrow or blood poses a significant challenge in diagnosing and treating AML. A substantial proportion of AML patients demonstrate resistance to induction chemotherapy and a grim prognosis upon relapse. The rapid advance in next generation sequencing technologies, such as single-cell RNA-sequencing (scRNA-seq), has revolutionized our understanding of AML pathogenesis by enabling high-resolution interrogation of the cellular heterogeneity in the AML ecosystem, and their transcriptional signatures at a single-cell level. New studies have successfully characterized the inextricably intertwined interactions among AML cells, immune cells and bone marrow microenvironment and their contributions to the AML development, therapeutic resistance and relapse. These findings have deepened and broadened our understanding the complexity and heterogeneity of AML, which are difficult to detect with bulk RNA-seq. This review encapsulates the burgeoning body of knowledge generated through scRNA-seq, providing the novel insights and discoveries it has unveiled in AML biology. Furthermore, we discuss the potential implications of scRNA-seq in therapeutic opportunities, focusing on immunotherapy. Finally, we highlight the current limitations and future direction of scRNA-seq in the field.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Center for Translational Medicine, Singapore, Singapore
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Center for Translational Medicine, Singapore, Singapore
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore, Singapore
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6
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Li J, Tang B, Miao Y, Li G, Sun Z. Targeting of STAT5 using the small molecule topotecan hydrochloride suppresses acute myeloid leukemia progression. Oncol Rep 2023; 50:208. [PMID: 37830151 PMCID: PMC10603551 DOI: 10.3892/or.2023.8645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023] Open
Abstract
Acute myeloid leukemia (AML) is a common type of acute leukemia in adults and relapse is one of the main reasons for treatment failure. FLT3‑ITD mutations are associated with poor prognosis, short disease‑free progression survival and high relapse rates in patients with AML. STAT5 is activated by FLT3‑ITD and drives the pathogenesis of AML. STAT5 activation is usually a hallmark of hematologic malignancies and occurs in ~70% of patients with AML. Moreover, STAT5 is a key molecule which regulates hematopoiesis, and its high expression is closely associated with drug resistance, thus direct targeting of STAT5 for AML is of great clinical value. The present study introduces a new small‑molecule inhibitor that targets STAT5, presenting a promising approach for AML therapy. A high throughput fluorescence polarization (FP) screening system for STAT5 was designed and established, and used to screen an existing compound library to obtain the highly active small molecule inhibitor, topotecan hydrochloride. Topotecan hydrochloride was demonstrated to be an effective inhibitor of STAT5 by molecular docking prediction and cellular thermal shift assay. Topotecan hydrochloride bound to STAT5, inhibiting its dimerization, phosphorylation and transcription of specific target genes. The compound exhibits cellular activity at the nanomolar level and significantly inhibits the proliferation of human AML cell lines and FLT3‑ITD+ AML cells. Furthermore, topotecan hydrochloride has the potential to exert an anti‑tumor effect in vivo. Overall, topotecan hydrochloride offers a new opportunity for the treatment of AML and other hematologic malignancies by directly targeting STAT5.
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Affiliation(s)
- Jiahui Li
- Fengxian Hospital Affiliated to Anhui University of Science and Technology, Shanghai 201499, P.R. China
| | - Bin Tang
- Department of Gynecology, East China Normal University Wuhu Affiliated Hospital (The Second People's Hospital of Wuhu City), Wuhu, Anhui 241000, P.R. China
| | - Ying Miao
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 201100, P.R. China
| | - Guihong Li
- Fengxian Hospital Affiliated to The Southern Medical University, Shanghai 201499, P.R. China
| | - Zhenliang Sun
- Fengxian Hospital Affiliated to Anhui University of Science and Technology, Shanghai 201499, P.R. China
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7
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Mu X, Chen C, Dong L, Kang Z, Sun Z, Chen X, Zheng J, Zhang Y. Immunotherapy in leukaemia. Acta Biochim Biophys Sin (Shanghai) 2023; 55:974-987. [PMID: 37272727 PMCID: PMC10326417 DOI: 10.3724/abbs.2023101] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/19/2023] [Indexed: 06/06/2023] Open
Abstract
Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has been made in basic research and preclinical studies for acute leukaemia compared to that of the many other types/subtypes of leukaemia, especially the exploration of the biological basis and application of immunotherapy in acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). In this review, we summarize the basic approaches to immunotherapy for leukaemia and focus on the research progress made in immunotherapy development for AML and ALL. Importantly, despite the advances made to date, big challenges still exist in the effectiveness of leukaemia immunotherapy, especially in AML. Therefore, we use AML as an example and summarize the mechanisms of tumour cell immune evasion, describe recently reported data and known therapeutic targets, and discuss the obstacles in finding suitable treatment targets and the results obtained in recent clinical trials for several types of single and combination immunotherapies, such as bispecific antibodies, cell therapies (CAR-T-cell treatment), and checkpoint blockade. Finally, we summarize novel immunotherapy strategies for treating lymphocytic leukaemia and clinical trial results.
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Affiliation(s)
- Xingmei Mu
- Hongqiao International Institute of MedicineShanghai Tongren Hospital/Faculty of Basic MedicineKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Chumao Chen
- Hongqiao International Institute of MedicineShanghai Tongren Hospital/Faculty of Basic MedicineKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Loujie Dong
- Shanghai Jiao Tong University School of MedicineShanghai200025China
| | - Zhaowei Kang
- Shanghai Jiao Tong University School of MedicineShanghai200025China
| | - Zhixian Sun
- Shanghai Jiao Tong University School of MedicineShanghai200025China
| | - Xijie Chen
- Shanghai Jiao Tong University School of MedicineShanghai200025China
| | - Junke Zheng
- Hongqiao International Institute of MedicineShanghai Tongren Hospital/Faculty of Basic MedicineKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Yaping Zhang
- Hongqiao International Institute of MedicineShanghai Tongren Hospital/Faculty of Basic MedicineKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
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8
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Discovery of a novel oral type Ⅰ CDK8 inhibitor against acute myeloid leukemia. Eur J Med Chem 2023; 251:115214. [PMID: 36889252 DOI: 10.1016/j.ejmech.2023.115214] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 03/08/2023]
Abstract
CDK8 plays a key role in acute myeloid leukemia, colorectal cancer and other cancers. Here, a total of 54 compounds were designed and synthesized. Among them, the most potent one compound 43 (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide), a novel CDK8 Ⅰ inhibitor, showed strong inhibitory activity against CDK8 (IC50 = 51.9 nM), good kinase selectivity, good anti AML cell proliferation activity (molm-13 GC50 = 1.57 ± 0.59 μM) and low toxicity in vivo (acute toxicity: 2000 mg/kg). Further mechanistic studies revealed that this compound could target CDK8 and then phosphorylate STAT-1 and STAT-5 thereby inhibiting of AML cell proliferation. In addition, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.
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9
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Haddadi N, Mirzania M, Ansarihadipour H. Syringic acid Attenuates Oxidative Stress in Plasma and Peripheral Blood Mononuclear Cells of Patients with Acute Myeloid Leukemia. Nutr Cancer 2023; 75:1038-1049. [PMID: 36697381 DOI: 10.1080/01635581.2023.2170432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Syringic acid (SA) is a natural phenolic acid that possesses antioxidant properties. The current study aimed to assess the possible ameliorative effects of SA on oxidative stress in patients with acute myeloid leukemia (AML). Twenty-two healthy donors as well as 22 sex- and age-matched AML patients participated in the study. AML patients were at the time of diagnosis and before remission. The peripheral blood mononuclear cells (PBMCs) and plasma samples were obtained and divided into four groups. The groups include: 1) buffer (B), containing isotonic phosphate buffer saline (100 mM, pH 7.4, 1 hr); 2) OX, containing solution subjected to iron-mediated oxidation (2.7 µM, 1 hr); 3) SA, containing SA solution (10 µM, 1 h) as ROS quencher and 4) SA + OX in which samples were pretreated with 10 µM of SA for 1 h, and then exposed to OX solution (2.7 µM) for 1 h. The results indicated that SA caused a significant increase in the activity of glutathione peroxidase (GPX) in PBMCs. Of note, the treatment of PBMCs and plasma samples of AML patients with SA was able to normalize the altered levels of GPX, superoxide dismutase (SOD), and catalase (CAT). The antioxidant effect of SA was further confirmed by analyzing the total oxidant status, lipid peroxidation, and protein carbonylation in both plasma samples and PBMCs of AML patients. According to the results, it seems that SA has strong protective effects on oxidative stress by elevating the total antioxidant status (TAS) of PBMCs and plasma specimens from AML patients.
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Affiliation(s)
- Naghmeh Haddadi
- Department of Biochemistry and Genetics, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mehrzad Mirzania
- Department of Internal Medicine, Cancer Research Center Cancer Institute, Imam Khomeini Science, Tehran, Iran
| | - Hadi Ansarihadipour
- Department of Biochemistry and Genetics, School of Medicine, Arak University of Medical Sciences, Arak, Iran
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10
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Mesbahi Y, Trahair TN, Lock RB, Connerty P. Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells. Front Oncol 2022; 12:807266. [PMID: 35223487 PMCID: PMC8867093 DOI: 10.3389/fonc.2022.807266] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/18/2022] [Indexed: 12/13/2022] Open
Abstract
Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.
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Affiliation(s)
- Yashar Mesbahi
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Toby N Trahair
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Richard B Lock
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Patrick Connerty
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
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11
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Nirachonkul W, Ogonoki S, Thumvijit T, Chiampanichayakul S, Panyajai P, Anuchapreeda S, Tima S, Chiampanichayakul S. CD123-Targeted Nano-Curcumin Molecule Enhances Cytotoxic Efficacy in Leukemic Stem Cells. NANOMATERIALS 2021; 11:nano11112974. [PMID: 34835741 PMCID: PMC8620973 DOI: 10.3390/nano11112974] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022]
Abstract
Acute myeloblastic leukemia (AML) is a disease with a high rate of relapse and drug resistance due to the remaining leukemic stem cells (LSCs). Therefore, LSCs are specific targets for the treatment of leukemia. CD123 is specifically expressed on LSCs and performs as a specific marker. Curcumin is the main active compound of a natural product with low toxicity for humans. It has been reported to inhibit leukemic cell growth. However, curcumin is practically insoluble in water and has low bioavailability. In this study, we aimed to formulate curcumin nanoparticles and conjugate with the anti-CD123 to overcome the low water solubility and improve the targeting of LSCs. The cytotoxicity of both curcumin-loaded PLGA/poloxamer nanoparticles (Cur-NPs) and anti-CD123-curcumin-loaded PLGA/poloxamer nanoparticles (anti-CD123-Cur-NPs) were examined in KG-1a cells. The results showed that Cur-NPs and Cur-NPs-CD123 exhibited cytotoxic effects on KG-1a cells with the IC50 values of 74.20 ± 6.71 and 41.45 ± 5.49 µM, respectively. Moreover, anti-CD123-Cur-NPs induced higher apoptosis than Cur-NPs. The higher uptake of anti-CD123-Cur-NPs in KG-1a cells was confirmed by using flow cytometry. In conclusion, the anti-CD123-Cur-NPs formulation improved curcumin's bioavailability and specific targeting of LSCs, suggesting that it is a promising drug delivery system for improving the therapeutic efficacy against AML.
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Affiliation(s)
- Wariya Nirachonkul
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (W.N.); (P.P.); (S.A.); (S.T.)
| | - Siriporn Ogonoki
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand;
- Research Center of Pharmaceutical Nanotechnology, Faculty Chiang Mai University, Chiang Mai 50200, Thailand
| | - Tarika Thumvijit
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | | | - Pawaret Panyajai
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (W.N.); (P.P.); (S.A.); (S.T.)
| | - Songyot Anuchapreeda
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (W.N.); (P.P.); (S.A.); (S.T.)
- Research Center of Pharmaceutical Nanotechnology, Faculty Chiang Mai University, Chiang Mai 50200, Thailand
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Singkome Tima
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (W.N.); (P.P.); (S.A.); (S.T.)
- Research Center of Pharmaceutical Nanotechnology, Faculty Chiang Mai University, Chiang Mai 50200, Thailand
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sawitree Chiampanichayakul
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; (W.N.); (P.P.); (S.A.); (S.T.)
- Research Center of Pharmaceutical Nanotechnology, Faculty Chiang Mai University, Chiang Mai 50200, Thailand
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
- Correspondence: ; Tel.: +66-5394-9237
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12
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Luo H, Zhang Y, Hu N, He Y, He C. Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia. Front Genet 2021; 12:715840. [PMID: 34630514 PMCID: PMC8498117 DOI: 10.3389/fgene.2021.715840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
Background: The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear. Methods: We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package edgeR was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein-protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results. Results: A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways. Conclusion: The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.
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Affiliation(s)
| | | | - Nan Hu
- Southwest Medical University, Luzhou, China
| | - Yancheng He
- Jiangyang City Construction College, Luzhou, China
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13
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Michelozzi IM, Kirtsios E, Giustacchini A. Driving CAR T Stem Cell Targeting in Acute Myeloid Leukemia: The Roads to Success. Cancers (Basel) 2021; 13:2816. [PMID: 34198742 PMCID: PMC8201025 DOI: 10.3390/cancers13112816] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/14/2022] Open
Abstract
Current treatment outcome for acute myeloid leukemia (AML) patients is unsatisfactory and characterized by high rates of relapse and poor overall survival. Increasing evidence points to a crucial role of leukemic stem cells (LSC) and the bone marrow (BM) leukemic niche, in which they reside, in AML evolution and chemoresistance. Thus, future strategies aiming at improving AML therapeutic protocols are likely to be directed against LSC and their niche. Chimeric antigen receptor (CAR) T-cells have been extremely successful in the treatment of relapsed/refractory acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma and comparable results in AML are highly desirable. At present, we are at the dawn of CAR T-cell application in AML, with several preclinical studies and few early phase clinical trials. However, the lack of leukemia-specific targets and the genetic and phenotypic heterogeneity of the disease combined with the leukemia-induced remodeling of the BM microenvironment are limiting CAR T-cell exploitation in AML. Here, we reviewed AML-LSC and AML-BM niche features in the context of their therapeutic targeting using CAR T-cells. We summarized recent progress in CAR T-cell application to the treatment of AML, and we discussed the remaining therapeutic challenges and promising novel strategies to overcome them.
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Affiliation(s)
- Ilaria M. Michelozzi
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London WC1N 1DZ, UK;
| | | | - Alice Giustacchini
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London WC1N 1DZ, UK;
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14
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Samimi A, Khodayar MJ, Alidadi H, Khodadi E. The Dual Role of ROS in Hematological Malignancies: Stem Cell Protection and Cancer Cell Metastasis. Stem Cell Rev Rep 2021; 16:262-275. [PMID: 31912368 DOI: 10.1007/s12015-019-09949-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Reactive oxygen species (ROS) play crucial role in hematopoiesis, regulation of differentiation, self-renewal, and the balance between quiescence and proliferation of hematopoietic stem cells (HSCs). The HSCs are a small population of undifferentiated cells that reside in the bone marrow (BM) and can undergo self-renewal by giving rise to mature cells. METHODS Relevant literature was identified through a PubMed search (2000-2019) of English-language papers using the following terms: reactive oxygen species, hematopoietic stem cell, leukemic stem cell, leukemia and chemotherapy. RESULTS HSCs are very sensitive to high levels of ROS and increased production of ROS have been attributed to HSC aging. HSC aging induced by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration. In addition, the elevated ROS levels might even trigger differentiation of Leukemic stem cells (LSCs) and ROS may be involved in the initiation and progression of hematological malignancies, such as leukemia. CONCLUSION Targeting genes involved in ROS in LSCs and HSCs are increasingly being used as a critical target for therapeutic interventions. Appropriate concentration of ROS may be an optimal therapeutic target for treatment of leukemia during chemotherapy, but still more studies are required to better understanding of the of ROS role in blood disorders.
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Affiliation(s)
- Azin Samimi
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Legal Medicine Organization, Legal Medicine Research Center, Ahvaz, Iran
| | - Mohammad Javad Khodayar
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadis Alidadi
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elahe Khodadi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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15
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Yang L, Zhang H, Yang X, Lu T, Ma S, Cheng H, Yen K, Cheng T. Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model. Front Oncol 2021; 11:659201. [PMID: 34123815 PMCID: PMC8190396 DOI: 10.3389/fonc.2021.659201] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/26/2021] [Indexed: 11/22/2022] Open
Abstract
Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.
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Affiliation(s)
- Liu Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Houyu Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Xue Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Ting Lu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Shihui Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Hui Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Kuangyu Yen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
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16
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HCK promotes glioblastoma progression by TGFβ signaling. Biosci Rep 2021; 40:225117. [PMID: 32484210 PMCID: PMC7300285 DOI: 10.1042/bsr20200975] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/03/2020] [Accepted: 05/27/2020] [Indexed: 12/20/2022] Open
Abstract
The hematopoietic cell kinase (HCK), a member of the Src family protein-tyrosine kinases (SFKs), is primarily expressed in cells of the myeloid and B lymphocyte lineages. Nevertheless, the roles of HCK in glioblastoma (GBM) remain to be examined. Thus, we aimed to investigate the effects of HCK on GBM development both in vitro and in vivo, as well as the underlying mechanism. The present study found that HCK was highly expressed in both tumor tissues from patients with GBM and cancer cell lines. HCK enhanced cell viability, proliferation, and migration, and induced cell apoptosis in vitro. Tumor xenografts results also demonstrated that HCK knockdown significantly inhibited tumor growth. Interestingly, gene set enrichment analysis (GSEA) showed HCK was closed associated with epithelial mesenchymal transition (EMT) and TGFβ signaling in GBM. In addition, we also found that HCK accentuates TGFβ-induced EMT, suggesting silencing HCK inhibited EMT through the inactivation of Smad signaling pathway. In conclusion, our findings indicated that HCK is involved in GBM progression via mediating EMT process, and may be served as a promising therapeutic target for GBM.
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17
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Lewis AC, Kats LM. Non-genetic heterogeneity, altered cell fate and differentiation therapy. EMBO Mol Med 2021; 13:e12670. [PMID: 33555144 PMCID: PMC7933953 DOI: 10.15252/emmm.202012670] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Altered capacity for self-renewal and differentiation is a hallmark of cancer, and many tumors are composed of cells with a developmentally immature phenotype. Among the malignancies where processes that govern cell fate decisions have been studied most extensively is acute myeloid leukemia (AML), a disease characterized by the presence of large numbers of "blasts" that resemble myeloid progenitors. Classically, the defining properties of AML cells were said to be aberrant self-renewal and a block of differentiation, and the term "differentiation therapy" was coined to describe drugs that promote the maturation of leukemic blasts. Notionally however, the simplistic view that such agents "unblock" differentiation is at odds with the cancer stem cell (CSC) hypothesis that posits that tumors are hierarchically organized and that CSCs, which underpin cancer growth, retain the capacity to progress to a developmentally more mature state. Herein, we will review recent developments that are providing unprecedented insights into non-genetic heterogeneity both at steady state and in response to treatment, and propose a new conceptual framework for therapies that aim to alter cell fate decisions in cancer.
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Affiliation(s)
| | - Lev M Kats
- The Peter MacCallum Cancer CentreMelbourneVICAustralia
- The Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVICAustralia
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18
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Arnone M, Konantz M, Hanns P, Paczulla Stanger AM, Bertels S, Godavarthy PS, Christopeit M, Lengerke C. Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity. Cancers (Basel) 2020; 12:E3742. [PMID: 33322769 PMCID: PMC7764578 DOI: 10.3390/cancers12123742] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging.
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Affiliation(s)
- Marlon Arnone
- Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; (M.A.); (M.K.); (P.H.)
| | - Martina Konantz
- Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; (M.A.); (M.K.); (P.H.)
| | - Pauline Hanns
- Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; (M.A.); (M.K.); (P.H.)
| | - Anna M. Paczulla Stanger
- Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.M.P.S.); (S.B.); (P.S.G.); (M.C.)
| | - Sarah Bertels
- Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.M.P.S.); (S.B.); (P.S.G.); (M.C.)
| | - Parimala Sonika Godavarthy
- Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.M.P.S.); (S.B.); (P.S.G.); (M.C.)
| | - Maximilian Christopeit
- Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.M.P.S.); (S.B.); (P.S.G.); (M.C.)
| | - Claudia Lengerke
- Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; (M.A.); (M.K.); (P.H.)
- Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.M.P.S.); (S.B.); (P.S.G.); (M.C.)
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19
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He X, Zhong X, Hu Z, Zhao S, Wei P, Li D. An insight into small extracellular vesicles: Their roles in colorectal cancer progression and potential clinical applications. Clin Transl Med 2020; 10:e249. [PMID: 33377655 PMCID: PMC7733319 DOI: 10.1002/ctm2.249] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and a leading cause of mortality worldwide. Small extracellular vesicles (sEVs) are nano-sized extracellular vesicles containing a variety of bioactive molecules, such as nucleic acids, proteins, lipids, and metabolites. Recent evidence from CRC has revealed that sEVs contribute to tumorigenesis, progression, and drug resistance, and serve as a tool for "liquid biopsy" and a drug delivery system for therapy. In this review, we summarize information about the roles of sEVs in the proliferation, invasion, migration, epithelial-mesenchymal transition, formation of the premetastatic niche, and drug resistance to elucidate the mechanisms governing sEVs in CRC and to identify novel targets for therapy and prognostic and diagnostic biomarkers.
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Affiliation(s)
- Xuefeng He
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xinyang Zhong
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Zijuan Hu
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Institute of PathologyFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Senlin Zhao
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Ping Wei
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Institute of PathologyFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Dawei Li
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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20
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Shen J, Lu Z, Wang J, Zhang T, Yang J, Li Y, Liu G, Zhang X. Advances of Nanoparticles for Leukemia Treatment. ACS Biomater Sci Eng 2020; 6:6478-6489. [PMID: 33320613 DOI: 10.1021/acsbiomaterials.0c01040] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Leukemia is a liquid tumor caused by a hematopoietic stem cell malignant clone, which seriously affects the normal function of the hematopoietic system. Conventional drugs have poor therapeutic effects due to their poor specificity and stability. With the development of nanotechnology, nonviral nanoparticles bring hope for the efficient treatment of leukemia. Nanoparticles are easily modified. They can be designed to target lesion sites and control drug release. Thereby, nanoparticles can improve the effects of drugs and reduce side effects. This review mainly focuses on and summarizes the current research progress of nanoparticles to deliver different leukemia therapeutic drugs, as to demonstrate the potential of nanoparticles in leukemia treatment.
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Affiliation(s)
- Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.,School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Zhiguo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.,School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Jianze Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Tianlu Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Yan Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Guiying Liu
- Department of Pediatrics, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing, 100029, PR China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
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21
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Zhou J, Quah JY, Ng Y, Chooi JY, Toh SHM, Lin B, Tan TZ, Hosoi H, Osato M, Seet Q, Ooi AL, Lindmark B, McHale M, Chng WJ. ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia. Haematologica 2020; 105:2286-2297. [PMID: 33054053 PMCID: PMC7556493 DOI: 10.3324/haematol.2019.230482] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/05/2019] [Indexed: 11/09/2022] Open
Abstract
Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | | | - Yvonne Ng
- Cancer Science Institute of Singapore, National University of Singapore
| | - Jing-Yuan Chooi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | | | - Baohong Lin
- Department of Hematology-Oncology, National University Cancer Institute, NUHS
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore
| | - Hiroki Hosoi
- Cancer Science Institute of Singapore, National University of Singapore
| | - Motomi Osato
- Cancer Science Institute of Singapore, National University of Singapore
- Department of Pediatrics, National University of Singapore, Yong Loo Lin School of Medicine
| | | | | | | | | | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
- Department of Hematology-Oncology, National University Cancer Institute, NUHS
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22
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Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauß A, Blaudszun AR, Yevsa T, Fricke S, Kossatz-Boehlert U. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol 2020; 11:1280. [PMID: 32849491 PMCID: PMC7426526 DOI: 10.3389/fimmu.2020.01280] [Citation(s) in RCA: 569] [Impact Index Per Article: 113.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
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Affiliation(s)
- Lia Walcher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Ann-Kathrin Kistenmacher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Reni Kitte
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Sarah Dluczek
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Alexander Strauß
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - André-René Blaudszun
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Stephan Fricke
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Uta Kossatz-Boehlert
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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23
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Mahalleh M, Shabani M, Rayzan E, Rezaei N. Reinforcing the primary immunotherapy modulators against acute leukemia; monoclonal antibodies in AML. Immunotherapy 2019; 11:1583-1600. [PMID: 31841068 DOI: 10.2217/imt-2019-0043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Recent therapeutic advances in cancer treatment recruit immune system potentiation against malignant cells. Numerous ongoing clinical trials on immunotherapy methods, either monotherapy or combination therapy, are investigating the impeding factors on the way of acute myeloid leukemia (AML) treatment. Due to the genetic diversity in AML progenitors, combining various strategies is more likely to be useful for improving patient outcomes. This review describes the details of applying monoclonal antibodies against AML, focusing on CD33, CD123, FLT3, CD45 and CD66 targeting. Furthermore, it clarifies the importance of immunotoxins, bispecific antibodies, chimeric antigen receptor (CAR)-T cells and T cell receptor-modified cells as reinforcing agents for monoclonal antibodies.
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Affiliation(s)
- Mehrdad Mahalleh
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahsima Shabani
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Elham Rayzan
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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24
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Yang XW, Sun K. [Research progress of single cell sequencing in the diagnosis and treatment of hematological diseases]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:443-446. [PMID: 31207715 PMCID: PMC7342236 DOI: 10.3760/cma.j.issn.0253-2727.2019.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- X W Yang
- Department of Hematology, Zhengzhou University People's Hospital, Henan Province People's Hospital, Zhengzhou 450003, China
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25
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Jia Y, Chng WJ, Zhou J. Super-enhancers: critical roles and therapeutic targets in hematologic malignancies. J Hematol Oncol 2019; 12:77. [PMID: 31311566 PMCID: PMC6636097 DOI: 10.1186/s13045-019-0757-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 06/14/2019] [Indexed: 12/11/2022] Open
Abstract
Super-enhancers (SEs) in a broad range of human cell types are large clusters of enhancers with aberrant high levels of transcription factor binding, which are central to drive expression of genes in controlling cell identity and stimulating oncogenic transcription. Cancer cells acquire super-enhancers at oncogene and cancerous phenotype relies on these abnormal transcription propelled by SEs. Furthermore, specific inhibitors targeting SEs assembly and activation have offered potential targets for treating various tumors including hematological malignancies. Here, we first review the identification, functional significance of SEs. Next, we summarize recent findings of SEs and SE-driven gene regulation in normal hematopoiesis and hematologic malignancies. The importance and various modes of SE-mediated MYC oncogene amplification are illustrated. Finally, we highlight the progress of SEs as selective therapeutic targets in basic research and clinical trials. Some open questions regarding functional significance and future directions of targeting SEs in the clinic will be discussed too.
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Affiliation(s)
- Yunlu Jia
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599 Republic of Singapore
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016 Zhejiang China
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599 Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Republic of Singapore
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228 Republic of Singapore
| | - Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599 Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Republic of Singapore
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26
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Darwish NHE, Sudha T, Godugu K, Bharali DJ, Elbaz O, El-Ghaffar HAA, Azmy E, Anber N, Mousa SA. Novel Targeted Nano-Parthenolide Molecule against NF-kB in Acute Myeloid Leukemia. Molecules 2019; 24:molecules24112103. [PMID: 31163672 PMCID: PMC6600366 DOI: 10.3390/molecules24112103] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 05/24/2019] [Accepted: 05/29/2019] [Indexed: 12/30/2022] Open
Abstract
The targeted nano-encapsulation of anticancer drugs can improve drug delivery and the selective targeting of cancer cells. Nuclear factor kappa B (NF-kB) is a regulator for different biological responses, including cell proliferation and differentiation. In acute myeloid leukemia (AML), constitutive NF-κB has been detected in more than 50% of cases, enabling leukemic cells to resist apoptosis and stimulate uncontrolled proliferation. We evaluated NF-kB expression in bone marrow samples from 103 patients with AML using quantitative real time polymerase chain reaction (RT-PCR) and found that expression was increased in 80.5% (83 out 103) of these patients with AML in comparison to the control group. Furthermore, overexpressed transmembrane glycoprotein (CD44) on leukemic cells in comparison to normal cells is known to play an important role in leukemic cell engraftment and survival. We designed poly lactide co-glycolide (PLGA) nanoparticles conjugated with antiCD44 and encapsulating parthenolide (PTL), a nuclear factor kappa B (NF-kB) inhibitor, in order to improve the selectivity and targeting of leukemic cells and to spare normal cells. In vitro, in leukemic cell lines Kasumi-1, KG-1a, and THP-1, proliferation was decreased by 40% (** p < 0.01) with 5 µM PLGA-antiCD44-PTL nanoparticles in comparison to the same concentration of free PTL (~10%). The higher uptake of the nanoparticles by leukemic cells was confirmed with confocal microscopy. In conclusion, PLGA-antiCD44-PTL nanoparticles improved the bioavailability and selective targeting of leukemic cells, thus holding promise as a drug delivery system to improve the cure rate of AML.
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Affiliation(s)
- Noureldien H E Darwish
- Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
| | - Thangirala Sudha
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
| | - Kavitha Godugu
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
| | - Dhruba J Bharali
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
| | - Osama Elbaz
- Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Hasan A Abd El-Ghaffar
- Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Emad Azmy
- Clinical Hematology Unit, Mansoura University Oncology Center, Mansoura University, Mansoura 35516, Egypt.
| | - Nahla Anber
- Fellow of Biochemistry Emergency Hospital, Mansoura University, Mansoura 35516, Egypt.
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
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27
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Sheng Y, Ji Z, Zhao H, Wang J, Cheng C, Xu W, Wang X, He Y, Liu K, Li L, Voeltzel T, Maguer-Satta V, Gao WQ, Zhu HH. Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells. Cell Prolif 2019; 52:e12611. [PMID: 31054182 PMCID: PMC6668982 DOI: 10.1111/cpr.12611] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/25/2019] [Accepted: 03/09/2019] [Indexed: 12/19/2022] Open
Abstract
Objectives Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain‐containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR‐ABL remain unclear. Materials and methods The level of SETD2 in imatinib‐sensitive and imatinib‐resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real‐time PCR. We analysed CD34+CD38− leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small‐molecule inhibitor JIB‐04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP‐quantitative PCR were performed to verify putative downstream targets. Results SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB‐04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect. Conclusions Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.
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Affiliation(s)
- Yaru Sheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongzhong Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Huifang Zhao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinming Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chaping Cheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Weimin Xu
- Department of Colorectal Surgery, Xin-Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xue Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yuman He
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kaiyuan Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Li
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | | | | | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Helen He Zhu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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28
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Ma H, Padmanabhan IS, Parmar S, Gong Y. Targeting CLL-1 for acute myeloid leukemia therapy. J Hematol Oncol 2019; 12:41. [PMID: 31014360 PMCID: PMC6480870 DOI: 10.1186/s13045-019-0726-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 03/27/2019] [Indexed: 02/05/2023] Open
Abstract
Despite major scientific discoveries and novel therapies over the past four decades, the treatment outcomes of acute myeloid leukemia (AML), especially in the adult patient population remain dismal. In the past few years, an increasing number of targets such as CD33, CD123, CLL-1, CD47, CD70, and TIM3, have been developed for immunotherapy of AML. Among them, CLL-1 has attracted the researchers’ attention due to its high expression in AML while being absent in normal hematopoietic stem cell. Accumulating evidence have demonstrated CLL-1 is an ideal target for AML. In this paper, we will review the expression of CLL-1 on normal cells and AML, the value of CLL-1 in diagnosis and follow-up, and targeting CLL-1 therapy-based antibody and chimeric antigen receptor T cell therapy as well as providing an overview of CLL-1 as a target for AML.
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Affiliation(s)
- Hongbing Ma
- Hematology Department, West China Hospital, Sichuan University, Chengdu, China
| | | | - Simrit Parmar
- Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Texas University, Houston, USA.
| | - Yuping Gong
- Hematology Department, West China Hospital, Sichuan University, Chengdu, China.
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29
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Fonseca ICCFE, da Luz FAC, Uehara IA, Silva MJB. Cell-adhesion molecules and their soluble forms: Promising predictors of "tumor progression" and relapse in leukemia. Tumour Biol 2018; 40:1010428318811525. [PMID: 30486756 DOI: 10.1177/1010428318811525] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept of cancer stem cells in carcinoma. Among these surface markers are proteins involved in cell-cell adhesion or cell-matrix adhesion, and they may play a role in the relapse of leukemia, similar to metastasis in carcinomas. The most important are epithelial cadherin, neural cadherin, epithelial cell-adhesion molecule, and CD44, which can be cleaved and released, and their soluble forms were found increased in serum levels of cancer patients, being implicated, in some cases, with progression, metastases, and relapse. In this review, we highlighted the role of these four adhesion molecules in carcinomas and hematological malignancies, mainly leukemia, and discuss if the serum levels of soluble forms can be correlated with the surface protein status on the leukemic cells. Accession of the soluble forms looks attractive, but their use as markers in cancer must be studied in association with other parameters, as there are significant changes in levels in other pathological conditions besides cancer. Studies correlating the levels of the forms with the status of the membrane-bound proteins in leukemic (stem) cells and correlating those parameters with relapse in leukemia may afford important knowledge and applicability of those serum markers in clinical practice. For instance, the expression of the membrane-bound forms of these adhesion proteins may have promising clinical use in leukemia and other hematological malignancies.
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Affiliation(s)
| | - Felipe Andrés Cordero da Luz
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
- 2 Nucleus of Cancer Prevention and Research, Cancer Hospital, Federal University of Uberlândia, Uberlândia, Brazil
| | - Isadora Akemi Uehara
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
| | - Marcelo José Barbosa Silva
- 1 Laboratory of Tumor Biomarkers and Osteoimmunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
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30
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Zhou J, Ng Y, Chng WJ. ENL: structure, function, and roles in hematopoiesis and acute myeloid leukemia. Cell Mol Life Sci 2018; 75:3931-3941. [PMID: 30066088 PMCID: PMC11105289 DOI: 10.1007/s00018-018-2895-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 07/16/2018] [Accepted: 07/27/2018] [Indexed: 01/09/2023]
Abstract
ENL/MLLT1 is a distinctive member of the KMT2 family based on its structural homology. ENL is a histone acetylation reader and a critical component of the super elongation complex. ENL plays pivotal roles in the regulation of chromatin remodelling and gene expression of many important proto-oncogenes, such as Myc, Hox genes, via histone acetylation. Novel insights of the key role of the YEATS domain of ENL in the transcriptional control of leukemogenic gene expression has emerged from whole genome Crisp-cas9 studies in acute myeloid leukemia (AML). In this review, we have summarized what is currently known about the structure and function of the ENL molecule. We described the ENL's role in normal hematopoiesis, and leukemogenesis. We have also outlined the detailed molecular mechanisms underlying the regulation of target gene expression by ENL, as well as its major interacting partners and complexes involved. Finally, we discuss the emerging knowledge of different approaches for the validation of ENL as a therapeutic target and the development of small-molecule inhibitors disrupting the YEATS reader pocket of ENL protein, which holds great promise for the treatment of AML. This review will not only provide a fundamental understanding of the structure and function of ENL and update on the roles of ENL in AML, but also the development of new therapeutic strategies.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
| | - Yvonne Ng
- Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore.
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31
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Shi M, Dong X, Huo L, Wei X, Wang F, Sun K. The Potential Roles and Advantages of Single Cell Sequencing in the Diagnosis and Treatment of Hematological Malignancies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1068:119-133. [DOI: 10.1007/978-981-13-0502-3_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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32
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Mambet C, Chivu-Economescu M, Matei L, Necula LG, Dragu DL, Bleotu C, Diaconu CC. Murine models based on acute myeloid leukemia-initiating stem cells xenografting. World J Stem Cells 2018; 10:57-65. [PMID: 29988882 PMCID: PMC6033712 DOI: 10.4252/wjsc.v10.i6.57] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 05/24/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells (LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to introduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.
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Affiliation(s)
- Cristina Mambet
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Mihaela Chivu-Economescu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania.
| | - Lilia Matei
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura Georgiana Necula
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Evaluation of in vitro effects of various targeted drugs on plasma cells and putative neoplastic stem cells in patients with multiple myeloma. Oncotarget 2018; 7:65627-65642. [PMID: 27582537 PMCID: PMC5323180 DOI: 10.18632/oncotarget.11593] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/13/2016] [Indexed: 01/08/2023] Open
Abstract
Multiple myeloma (MM) is a malignancy characterized by monoclonal paraproteinemia and tissue plasmocytosis. In advanced MM cytopenia and osteopathy may occur. Although several effective treatment strategies have been developed in recent years, there is still a need to identify new drug targets and to develop more effective therapies for patients with advanced MM. We examined the effects of 15 targeted drugs on growth and survival of primary MM cells and 5 MM cell lines (MM.1S, NCI-H929, OPM-2, RPMI-8226, U-266). The PI3-kinase blocker BEZ235, the pan-BCL-2 inhibitor obatoclax, the Hsp90-targeting drug 17AAG, and the Polo-like kinase-1 inhibitor BI2536, were found to exert major growth-inhibitory effects in all 5 MM cell lines tested. Moreover, these drugs suppressed the in vitro proliferation of primary bone marrow-derived MM cells and induced apoptosis at pharmacologic drug concentrations. Apoptosis-inducing effects were not only seen in the bulk of MM cells but also in MM stem cell-containing CD138−/CD20+/CD27+ memory B-cell fractions. Synergistic growth-inhibitory effects were observed in MM cell lines using various drug combinations, including 17AAG+BI2536 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+BEZ235 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+obatoclax in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+BEZ235 in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+obatoclax in MM.1S, OPM-2 and RPMI-8226 cells, and BEZ235+obatoclax in MM.1S and RPMI-8226 cells. Together, our data show that various targeted drugs induce profound and often synergistic anti-neoplastic effects in MM cells which may have clinical implications and may contribute to the development of novel treatment strategies in advanced MM.
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Zhou J, Toh SHM, Chan ZL, Quah JY, Chooi JY, Tan TZ, Chong PSY, Zeng Q, Chng WJ. A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase. J Hematol Oncol 2018; 11:36. [PMID: 29514683 PMCID: PMC5842526 DOI: 10.1186/s13045-018-0581-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 02/27/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor. METHODS In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism. RESULTS The list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/β-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/β-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/β-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells. CONCLUSIONS In summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/β-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Zit-Liang Chan
- Cancer Science Institute of Singapore, Singapore, Singapore
| | | | - Jing-Yuan Chooi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, Singapore, Singapore
- Translational Centre for Development and Research, National University Health System, Singapore, Singapore
| | | | - Qi Zeng
- Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228 Singapore
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Ji Q, Ding YH, Sun Y, Zhang Y, Gao HE, Song HN, Yang M, Liu XL, Zhang ZX, Li YH, Gao YD. Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells. Oncotarget 2018; 7:65012-65023. [PMID: 27542251 PMCID: PMC5323134 DOI: 10.18632/oncotarget.11342] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 08/09/2016] [Indexed: 12/11/2022] Open
Abstract
Leukemic stem cells (LSCs) greatly contribute to the initiation, relapse, and multidrug resistance of leukemia. Current therapies targeting the cell cycle and rapidly growing leukemic cells, including conventional chemotherapy, have little effect due to the self-renewal and differentiated malignant cells replenishment ability of LSCs despite their scarce supply in the bone marrow. Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) which was discovered in michelia compressa and michelia champaca plants, and has been shown to exert selective cytotoxic effects on CD34+CD38− LSCs. In this study, we demonstrate that DMAMCL significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML). Mechanistic investigations further revealed that MCL exerted its cytotoxic effects via inhibition of NF-κB expression and activity, and by generating intracellular reactive oxygen species (ROS). These results provide valuable insight into the mechanisms underlying MCL-induced cytotoxicity of LSCs, and support further preclinical investigations of MCL-related therapies for the treatment of AML.
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Affiliation(s)
- Qing Ji
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Ya-Hui Ding
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.,The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Yue Sun
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Yu Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Hui-Er Gao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - He-Nan Song
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Ming Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Xiao-Lei Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Zi-Xiang Zhang
- Department of Stomatology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Ying-Hui Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
| | - Ying-Dai Gao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
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Darwish NHE, Sudha T, Godugu K, Elbaz O, Abdelghaffar HA, Hassan EEA, Mousa SA. Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1. Oncotarget 2018; 7:57811-57820. [PMID: 27506934 PMCID: PMC5295391 DOI: 10.18632/oncotarget.11063] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/19/2016] [Indexed: 12/15/2022] Open
Abstract
Acute myeloid leukemia (AML) patients show high relapse rates and some develop conventional chemotherapy resistance. Leukemia Stem Cells (LSCs) are the main player for AML relapses and drug resistance. LSCs might rely on the B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) in promoting cellular proliferation and survival. Growth of LSCs in microenvironments that are deprived of nutrients leads to up-regulation of the signaling pathways during the progression of the disease, which may illustrate the sensitivity of LSCs to inhibitors of those signaling pathways as compared to normal cells. We analyzed the expression of LSC markers (CD34, CLL-1, TIM-3 and BMI-1) using quantitative RT-PCR in bone marrow samples of 40 AML patients of different FAB types (M1, M2, M3, M4, M5, and M7). We also studied the expression of these markers in 2 AML cell lines (Kasumi-1 and KG-1a) using flow cytometry and quantitative RT-PCR. The overexpression of TIM-3, CLL-1, and BMI-1 was markedly correlated with poor prognosis in these patients. Our in vitro findings demonstrate that targeting BMI-1, which markedly increased in the leukemic cells, was associated with marked decrease in leukemic burden. This study also presents results for blocking LSCs' surface markers CD44, CLL-1, and TIM-3. These markers may play an important role in elimination of AML. Our study indicates a correlation between the expression of markers TIM-3, CLL-1, and especially of BMI-1 and the aggressiveness of AML and thus the potential impact of prognosis and therapies that target LSCs on improving the cure rates.
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Affiliation(s)
- Noureldien H E Darwish
- Faculty of Medicine, Mansoura University, Mansoura, Egypt.,The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
| | - Thangirala Sudha
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
| | - Kavitha Godugu
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
| | - Osama Elbaz
- Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | | | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
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Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia 2018; 32:1135-1146. [PMID: 29472718 PMCID: PMC5940656 DOI: 10.1038/s41375-017-0005-9] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/30/2017] [Accepted: 12/06/2017] [Indexed: 12/13/2022]
Abstract
The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4–130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4–130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4–130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4–130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4–130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.
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38
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Liu FR, Jin H, Wang Y, Chen C, Li M, Mao SJ, Wang Q, Li H. Anti-CD123 antibody-modified niosomes for targeted delivery of daunorubicin against acute myeloid leukemia. Drug Deliv 2017; 24:882-890. [PMID: 28574300 PMCID: PMC8244627 DOI: 10.1080/10717544.2017.1333170] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
A novel niosomal delivery system was designed and investigated for the targeted delivery of daunorubicin (DNR) against acute myeloid leukemia (AML). Anti-CD123 antibodies conjugated to Mal-PEG2000-DSPE were incorporated into normal niosomes (NS) via a post insertion method to afford antibody-modified niosomes (CD123-NS). Next, NS was modified with varying densities of antibody (0.5 or 2%, antibody/Span 80, molar ratio), thus providing L-CD123-NS and H-CD123-NS. We studied the effect of antibody density on the uptake efficiency of niosomes in NB4 and THP-1 cells, on which CD123 express differently. Our results demonstrate CD123-NS showed significantly higher uptake efficiency than NS in AML cells, and the uptake efficiency of CD123-NS has been ligand density-dependent. Also, AML cells preincubated with anti-CD123 antibody showed significantly reduced cellular uptake of CD123-NS compared to control. Further study on the uptake mechanism confirmed a receptor-mediated endocytic process. Daunorubicin (DNR)-loaded H-CD123-NS demonstrated a 2.45- and 3.22-fold higher cytotoxicity, compared to DNR-loaded NS in NB4 and THP-1 cells, respectively. Prolonged survival time were observed in leukemic mice treated with DNR-H-CD123-NS. Collectively, these findings support that the CD123-NS represent a promising delivery system for the treatment of AML.
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Affiliation(s)
- Fu-Rong Liu
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Hui Jin
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Yin Wang
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Chen Chen
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Ming Li
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Sheng-Jun Mao
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Qiantao Wang
- a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education and West China School of Pharmacy , Sichuan University , Chengdu , China
| | - Hui Li
- b Department of Hematology , Sichuan Academy of Medical Sciences and Sichuan Provincial People Hospital , Chengdu , China
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Zhang CC, Yan Z, Pascual B, Jackson-Fisher A, Huang DS, Zong Q, Elliott M, Fan C, Huser N, Lee J, Sung M, Sapra P. Gemtuzumab Ozogamicin (GO) Inclusion to Induction Chemotherapy Eliminates Leukemic Initiating Cells and Significantly Improves Survival in Mouse Models of Acute Myeloid Leukemia. Neoplasia 2017; 20:1-11. [PMID: 29172076 PMCID: PMC5702869 DOI: 10.1016/j.neo.2017.10.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 10/29/2017] [Accepted: 10/30/2017] [Indexed: 12/23/2022] Open
Abstract
Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing a modified dosing regimen of GO can be safely combined with induction chemotherapy, and the combination provides significant survival benefits in AML patients. Here we tested whether the survival benefits seen with the combination arise from the enhanced reduction of chemoresidual disease and leukemic initiating cells (LICs). Herein, we use cell line and patient-derived xenograft (PDX) AML models to evaluate the combination of GO with daunorubicin and cytarabine (DA) induction chemotherapy on AML blast growth and animal survival. DA chemotherapy and GO as separate treatments reduced AML burden but left significant chemoresidual disease in multiple AML models. The combination of GO and DA chemotherapy eliminated nearly all AML burden and extended overall survival. In two small subsets of AML models, chemoresidual disease following DA chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34). In vivo, the two chemoresistant subpopulations (CLL1+/CD117− and CD34+/CD38+) showed higher ability to self-renewal than their counterpart subpopulations, respectively. CD33 was coexpressed in these functional LIC subpopulations. We demonstrate that the GO and DA induction chemotherapy combination more effectively eliminates LICs in AML PDX models than either single agent alone. These data suggest that the survival benefit seen by the combination of GO and induction chemotherapy, nonclinically and clinically, may be attributed to the enhanced reduction of LICs.
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Affiliation(s)
- Cathy C Zhang
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA.
| | - Zhengming Yan
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | - Bernadette Pascual
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | - Amy Jackson-Fisher
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | | | - Qing Zong
- Pfizer Worldwide Research and Development, Drug Safety Research and Development Group, La Jolla, CA
| | - Mark Elliott
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | - Conglin Fan
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | - Nanni Huser
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
| | - Joseph Lee
- Pfizer Worldwide Research and Development, Oncology Research Unit, La Jolla, CA
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Zhou J, Li XL, Chen ZR, Chng WJ. Tumor-derived exosomes in colorectal cancer progression and their clinical applications. Oncotarget 2017; 8:100781-100790. [PMID: 29246022 PMCID: PMC5725064 DOI: 10.18632/oncotarget.20117] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/30/2017] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) ranks as the third leading cause of cancer mortality in both of men and women worldwide due to its metastatic properties and resistance to current treatment. Recent studies have shown that tumor-derived exosomes play emerging roles in the development of cancer. Exosomes are nano-sized extracellular vesicles (EVs) that contain lipids, proteins, DNAs, and RNA species (mRNA, miRNA, long non-coding RNA). These exosomal cargos can be transferred locally and systemically, after taken by recipient cells, so exosomes represent a new form of intercellular communication. There is increasing evidence demonstrating that exosomes control a wide range of pathways bolstering tumor development, metastasis and drug resistance. This review provides an in-depth and timely summary of the role of exosomes in CRC. We first describe the common features and biogenesis of exosomes. We then highlight important findings that support the emerging roles of exosomes in CRC cell growth, invasion and metastasis, as well as resistance to treatment. Finally, we discuss the clinical application of exosomes as diagnostic biomarkers, in vivo drug delivery system and the potential of novel exosome-based immunotherapy for CRC.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore
| | - Xiao-Lan Li
- Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215001, China
| | - Zhi-Rong Chen
- Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215001, China
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore 119228, Republic of Singapore
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Chen J, Wei H, Cheng J, Xie B, Wang B, Yi J, Tian B, Liu Z, Wang F, Zhang Z. Characteristics of doxorubicin-selected multidrug-resistant human leukemia HL-60 cells with tolerance to arsenic trioxide and contribution of leukemia stem cells. Oncol Lett 2017; 15:1255-1262. [PMID: 29399180 DOI: 10.3892/ol.2017.7353] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 06/09/2017] [Indexed: 01/26/2023] Open
Abstract
The present study selected and characterized a multidrug-resistant HL-60 human acute promyelocytic leukemia cell line, HL-60/RS, by exposure to stepwise incremental doses of doxorubicin. The drug-resistant HL-60/RS cells exhibited 85.68-fold resistance to doxorubicin and were cross-resistant to other chemotherapeutics, including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. The cells over-expressed the transporters P-glycoprotein, multidrug-resistance-related protein 1 and breast-cancer-resistance protein, encoded by the adenosine triphosphate-binding cassette (ABC)B1, ABCC1 and ABCG2 genes, respectively. Unlike other recognized chemoresistant leukemia cell lines, HL-60/RS cells were also strongly cross-resistant to arsenic trioxide. The proportion of leukemia stem cells (LSCs) increased synchronously with increased of drug resistance in the doxorubicin-induced HL-60 cell population. The present study confirmed that doxorubicin-induced HL-60 cells exhibited multidrug-resistance and high arsenic-trioxide resistance. Drug-resistance in these cells may be due to surviving chemoresistant LSCs in the HL-60 population, which have been subjected to long and consecutive selection by doxorubicin.
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Affiliation(s)
- Jing Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Hulai Wei
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Jie Cheng
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Bei Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Bei Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Juan Yi
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Baoying Tian
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Zhuan Liu
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Feifei Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Zhewen Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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Paprocka M, Bielawska-Pohl A, Rossowska J, Krawczenko A, Duś D, Kiełbiński M, Haus O, Podolak-Dawidziak M, Kuliczkowski K. MRP1 protein expression in leukemic stem cells as a negative prognostic marker in acute myeloid leukemia patients. Eur J Haematol 2017; 99:415-422. [DOI: 10.1111/ejh.12938] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2017] [Indexed: 12/23/2022]
Affiliation(s)
- Maria Paprocka
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; The Polish Academy of Sciences; Wroclaw Poland
| | - Aleksandra Bielawska-Pohl
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; The Polish Academy of Sciences; Wroclaw Poland
| | - Joanna Rossowska
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; The Polish Academy of Sciences; Wroclaw Poland
| | - Agnieszka Krawczenko
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; The Polish Academy of Sciences; Wroclaw Poland
| | - Danuta Duś
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; The Polish Academy of Sciences; Wroclaw Poland
| | - Marek Kiełbiński
- Department and Clinic of Hematology; Blood Neoplasms and Bone Marrow Transplantation; Wroclaw Medical University; Wroclaw Poland
| | - Olga Haus
- Department and Clinic of Hematology; Blood Neoplasms and Bone Marrow Transplantation; Wroclaw Medical University; Wroclaw Poland
| | - Maria Podolak-Dawidziak
- Department and Clinic of Hematology; Blood Neoplasms and Bone Marrow Transplantation; Wroclaw Medical University; Wroclaw Poland
| | - Kazimierz Kuliczkowski
- Department and Clinic of Hematology; Blood Neoplasms and Bone Marrow Transplantation; Wroclaw Medical University; Wroclaw Poland
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Zhou J, Bi C, Ching YQ, Chooi JY, Lu X, Quah JY, Toh SHM, Chan ZL, Tan TZ, Chong PSY, Chng WJ. Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia. J Hematol Oncol 2017; 10:138. [PMID: 28693523 PMCID: PMC5504806 DOI: 10.1186/s13045-017-0507-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 06/29/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Current conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment. The relapse is postulated to be due to leukemia stem cells (LSCs), which are different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive. METHODS We modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle, and colony-forming assays. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools. AML mouse xenograft model was used to examine the in vivo function of LIN28B. RESULTS We demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Data point to a mechanism where that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, ectopic expression of LIN28B increased tumorigenicity, while silencing LIN28B led to slow tumor growth in vivo. CONCLUSIONS In sum, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.
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MESH Headings
- Animals
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cell Proliferation
- Female
- Gene Expression Regulation, Leukemic
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Mice
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA Interference
- RNA, Small Interfering/genetics
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Republic of Singapore
| | - Chonglei Bi
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Ying Qing Ching
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Jing-Yuan Chooi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Republic of Singapore
| | - Xiao Lu
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Jessie Yiying Quah
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Sabrina Hui-Min Toh
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Zit-Liang Chan
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Phyllis SY Chong
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599 Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Republic of Singapore
- Department of Hematology-Oncology, National University Cancer institute of Singapore, The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228 Republic of Singapore
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44
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Izzi V, Lakkala J, Devarajan R, Ruotsalainen H, Savolainen ER, Koistinen P, Heljasvaara R, Pihlajaniemi T. An extracellular matrix signature in leukemia precursor cells and acute myeloid leukemia. Haematologica 2017; 102:e245-e248. [PMID: 28411251 DOI: 10.3324/haematol.2017.167304] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Valerio Izzi
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Juho Lakkala
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Raman Devarajan
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Heli Ruotsalainen
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Eeva-Riitta Savolainen
- Nordlab Oulu and Institute of Diagnostics, Department of Clinical Chemistry, Oulu University Hospital, Finland.,Medical Research Center Oulu, Institute of Clinical Medicine, Oulu University Hospital, Finland
| | - Pirjo Koistinen
- Medical Research Center Oulu, Institute of Clinical Medicine, Oulu University Hospital, Finland
| | - Ritva Heljasvaara
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland.,Centre for Cancer Biomarkers (CCBIO), Department of Biomedicine, University of Bergen, Norway
| | - Taina Pihlajaniemi
- Centre of Excellence in Cell-Extracellular Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
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45
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Madhumathi J, Sridevi S, Verma RS. CD25 targeted therapy of chemotherapy resistant leukemic stem cells using DR5 specific TRAIL peptide. Stem Cell Res 2017; 19:65-75. [DOI: 10.1016/j.scr.2017.01.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/24/2016] [Accepted: 01/03/2017] [Indexed: 12/13/2022] Open
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46
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Zhou J, Chan ZL, Bi C, Lu X, Chong PSY, Chooi JY, Cheong LL, Liu SC, Ching YQ, Zhou Y, Osato M, Tan TZ, Ng CH, Ng SB, Wang S, Zeng Q, Chng WJ. LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. Mol Cancer Res 2017; 15:294-303. [PMID: 28011885 DOI: 10.1158/1541-7786.mcr-16-0275-t] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/29/2016] [Accepted: 11/18/2016] [Indexed: 12/17/2022]
Abstract
PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis.Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. ©2016 AACR.
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Affiliation(s)
- Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - Zit-Liang Chan
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Chonglei Bi
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Xiao Lu
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Phyllis S Y Chong
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Jing-Yuan Chooi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - Lip-Lee Cheong
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Shaw-Cheng Liu
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Ying Qing Ching
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Yafeng Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Motomi Osato
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
| | - Chin Hin Ng
- Department of Haematology-Oncology, National University Cancer Institute, NUHS, Singapore, Republic of Singapore
| | - Siok-Bian Ng
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore
- Department of Pathology, National University Hospital, Singapore, Republic of Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Qi Zeng
- Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Republic of Singapore
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
- Department of Haematology-Oncology, National University Cancer Institute, NUHS, Singapore, Republic of Singapore
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47
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Roversi FM, Pericole FV, Machado-Neto JA, da Silva Santos Duarte A, Longhini AL, Corrocher FA, Palodetto B, Ferro KP, Rosa RG, Baratti MO, Verjovski-Almeida S, Traina F, Molinari A, Botta M, Saad STO. Hematopoietic cell kinase (HCK) is a potential therapeutic target for dysplastic and leukemic cells due to integration of erythropoietin/PI3K pathway and regulation of erythropoiesis. Biochim Biophys Acta Mol Basis Dis 2017; 1863:450-461. [DOI: 10.1016/j.bbadis.2016.11.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 10/14/2016] [Accepted: 11/08/2016] [Indexed: 12/20/2022]
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48
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Siveen KS, Uddin S, Mohammad RM. Targeting acute myeloid leukemia stem cell signaling by natural products. Mol Cancer 2017; 16:13. [PMID: 28137265 PMCID: PMC5282735 DOI: 10.1186/s12943-016-0571-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 12/19/2016] [Indexed: 12/11/2022] Open
Abstract
Acute myeloid leukemia (AML) is the most commonly diagnosed leukemia in adults (25%) and comprises 15-20% in children. It is a genetically heterogeneous aggressive disease characterized by the accumulation of somatically acquired genetic changes, altering self-renewal, proliferation, and differentiation of hematopoietic progenitor cells, resulting in uncontrolled clonal proliferation of malignant progenitor myeloid cells in the bone marrow, peripheral blood, and occasionally in other body tissues. Treatment with modern chemotherapy regimen (cytarabine and daunorubicin) usually achieves high remission rates, still majority of patients are found to relapse, resulting in only 40-45% overall 5 year survival in young patients and less than 10% in the elderly AML patients. The leukemia stem cells (LSCs) are characterized by their unlimited self-renewal, repopulating potential and long residence in a quiescent state of G0/G1 phase. LSCs are considered to have a pivotal role in the relapse and refractory of AML. Therefore, new therapeutic strategies to target LSCs with limited toxicity towards the normal hematopoietic population is critical for the ultimate curing of AML. Ongoing research works with natural products like parthenolide (a natural plant extract derived compound) and its derivatives, that have the ability to target multiple pathways that regulate the self-renewal, growth and survival of LSCs point to ways for a possible complete remission in AML. In this review article, we will update and discuss various natural products that can target LSCs in AML.
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Affiliation(s)
- Kodappully Sivaraman Siveen
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
| | - Ramzi M Mohammad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, Qatar
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49
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Amanzadeh A, Heidarnejad F, Abdollahpour-Alitappeh M, Molla-Kazemiha V, Yari S, Hadizadeh-Tasbiti A, Habibi-Anbouhi M, Abolhassani M, Shokrgozar MA. Development of high-affinity monoclonal antibody using CD44 overexpressed cells as a candidate for targeted immunotherapy and diagnosis of acute myeloid leukemia. Hum Antibodies 2017; 26:7-15. [PMID: 28269763 DOI: 10.3233/hab-170315] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
AIM CD44s antigens have been suggested as an efficient biomarker for cancer stem cells. Current study aimed to develop a hybridoma that producing a high affinity murine anti-human CD44 monoclonal antibody for early diagnostic laboratory tests of some cancer. MATERIALS AND METHODS To make hybridoma against CD44, mice were immunized with MDA-MB-468 cells. Resulted hybridomas using three culture media were screened by indirect ELISA, then cloned by limiting dilution, and isotype was determined after obtaining ascitic fluid and antibody purification. RESULTS We obtained a stable secreting clone, capable of secreting a high-affinity monoclonal antibody against CD44 protein, IgG2a kappa, with the affinity of 5.4 × 10-8 M without cross-reactivity. CONCLUSION We could establish a hybridoma in a native form. This stable and high-affinity anti-CD44 mAb has a potential for diagnostic procedures and laboratory research. Thus, it could be exploited as a suitable tool for target-specific diagnosis and even treatment in several cancers.
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MESH Headings
- Animals
- Antibodies, Monoclonal/biosynthesis
- Antibodies, Monoclonal/isolation & purification
- Antibody Affinity
- Antibody Specificity
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/immunology
- Cell Line, Tumor
- Clone Cells
- Female
- Gene Expression
- Humans
- Hyaluronan Receptors/genetics
- Hyaluronan Receptors/immunology
- Hybridomas/cytology
- Hybridomas/immunology
- Immunization
- Immunoglobulin G/biosynthesis
- Immunoglobulin G/isolation & purification
- Immunotherapy/methods
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Mice
- Mice, Inbred BALB C
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Affiliation(s)
- Amir Amanzadeh
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | | | | | | | - Shamsi Yari
- Department of Mycobacteriology, Pasteur Institute of Iran, Tehran, Iran
| | | | | | - Mohsen Abolhassani
- Immunology Department, Hybridoma Laboratory, Pasteur Institute of Iran, Tehran, Iran
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50
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Stahl M, Kim TK, Zeidan AM. Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities. World J Stem Cells 2016; 8:316-331. [PMID: 27822339 PMCID: PMC5080639 DOI: 10.4252/wjsc.v8.i10.316] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/11/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.
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