|
1
|
E VB, Ranganath Pai KS. Stem Cells and Tumor-Killing Virus to Target Brain Tumor: In Pursuit to Bring a Potential Delivery Vehicle for the Central Nervous System Tumors. Curr Drug Deliv 2024; 21:2-15. [PMID: 36825709 DOI: 10.2174/1567201820666230220101052] [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: 07/05/2022] [Revised: 12/08/2022] [Accepted: 12/28/2022] [Indexed: 02/22/2023]
Abstract
To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.
Collapse
Affiliation(s)
- Vignesh Balaji E
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| |
Collapse
|
|
2
|
Li YR, Dunn ZS, Yu Y, Li M, Wang P, Yang L. Advancing cell-based cancer immunotherapy through stem cell engineering. Cell Stem Cell 2023; 30:592-610. [PMID: 36948187 PMCID: PMC10164150 DOI: 10.1016/j.stem.2023.02.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 01/04/2023] [Accepted: 02/22/2023] [Indexed: 03/24/2023]
Abstract
Advances in cell-based therapy, particularly CAR-T cell therapy, have transformed the treatment of hematological malignancies. Although an important step forward for the field, autologous CAR-T therapies are hindered by high costs, manufacturing challenges, and limited efficacy against solid tumors. With ongoing progress in gene editing and culture techniques, engineered stem cells and their application in cell therapy are poised to address some of these challenges. Here, we review stem cell-based immunotherapy approaches, stem cell sources, gene engineering and manufacturing strategies, therapeutic platforms, and clinical trials, as well as challenges and future directions for the field.
Collapse
Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zachary Spencer Dunn
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
| | - Yanqi Yu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Miao Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| |
Collapse
|
|
3
|
Chen YF, Li J, Xu LL, Găman MA, Zou ZY. Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities. World J Clin Cases 2023; 11:268-291. [PMID: 36686358 PMCID: PMC9850970 DOI: 10.12998/wjcc.v11.i2.268] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/02/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
As an important treatment for acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) plays an important role in reducing relapse and improving long-term survival. With rapid advancements in basic research in molecular biology and immunology and with deepening understanding of the biological characteristics of hematopoietic stem cells, allo-HSCT has been widely applied in clinical practice. During allo-HSCT, preconditioning, the donor, and the source of stem cells can be tailored to the patient's conditions, greatly broadening the indications for HSCT, with clear survival benefits. However, the risks associated with allo-HSCT remain high, i.e. hematopoietic reconstitution failure, delayed immune reconstitution, graft-versus-host disease, and post-transplant relapse, which are bottlenecks for further improvements in allo-HSCT efficacy and have become hot topics in the field of HSCT. Other bottlenecks recognized in the current treatment of individuals diagnosed with acute myeloid leukemia and subjected to allo-HSCT include the selection of the most appropriate conditioning regimen and post-transplantation management. In this paper, we reviewed the progress of relevant research regarding these aspects.
Collapse
Affiliation(s)
- Yong-Feng Chen
- Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jing Li
- Department of Histology and Embryology, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Ling-Long Xu
- Department of Hematology, Taizhou Central Hospital, Taizhou 318000, Zhejiang Province, China
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
| | - Zhen-You Zou
- Department of Scientific Research,Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou 545005, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
4
|
Zhao ZS, Shao W, Liu JK. Autologous or allogeneic hematopoietic stem cells transplantation combined with high-dose chemotherapy for refractory neuroblastoma: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e28096. [PMID: 34889262 PMCID: PMC8663834 DOI: 10.1097/md.0000000000028096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Neuroblastoma is a common solid malignant tumor in children. Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor. High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation might improve survival of patients with refractory neuroblastoma. In this study, we aimed to summarize the efficacy of autologous or allogeneic HSC transplantation combined with high-dose chemotherapy for patients with refractory neuroblastoma through the meta-analysis. METHODS AND ANALYSIS Relevant clinical trials of autologous or allogeneic HSC transplantation for the treatment refractory neuroblastoma patients will be searched in Web of Science, Cochrane Library, PubMed, Google Scholar, Embase, Medline, China National Knowledge Infrastructure, China Scientific Journal Database, Chinese Biomedical Literature Database and Wanfang Database from their inception to December 2020. Two researchers will perform data extraction and risk of bias assessment independently. The clinical outcomes including tumor response, overall survival, event-free survival (EFS), quality of life (QoL) and adverse events, were systematically evaluated by using Review Manager 5.3 and Stata 14.0 statistical software. RESULTS The results of this study will provide high-quality evidence for the effect of autologous or allogeneic HSC transplantation combined with high-dose chemotherapy on tumor response, survival, and QoL in patients with refractory neuroblastoma. CONCLUSIONS The conclusions of this meta-analysis will be published in a peer-reviewed journal, and provide more evidence-based guidance in clinical practice.
Collapse
|
|
5
|
Li YR, Zhou Y, Kramer A, Yang L. Engineering stem cells for cancer immunotherapy. Trends Cancer 2021; 7:1059-1073. [PMID: 34479851 DOI: 10.1016/j.trecan.2021.08.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/04/2021] [Accepted: 08/04/2021] [Indexed: 12/27/2022]
Abstract
Engineering stem cells presents an attractive paradigm for cancer immunotherapy. Stem cells engineered to stably express various chimeric antigen receptors (CARs) or T-cell receptors (TCRs) against tumor-associated antigens are showing increasing promise in the treatment of solid tumors and hematologic malignancies. Stem cells engraft for long-term immune cell generation and serve as a sustained source of tumor-specific effector cells to maintain remissions. Furthermore, engineering stem cells provides 'off-the-shelf' cellular products, obviating the need for a personalized and patient-specific product that plagues current autologous cell therapies. Herein, we summarize recent progress of stem cell-engineered cancer therapies, and discuss the utility, impact, opportunities, and challenges of cellular engineering that may facilitate the translational and clinical research.
Collapse
Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yang Zhou
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Adam Kramer
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
| |
Collapse
|
|
6
|
Bao G, Xu R, Wang X, Ji J, Wang L, Li W, Zhang Q, Huang B, Chen A, Zhang D, Kong B, Yang Q, Yuan C, Wang X, Wang J, Li X. Identification of lncRNA Signature Associated With Pan-Cancer Prognosis. IEEE J Biomed Health Inform 2021; 25:2317-2328. [PMID: 32991297 DOI: 10.1109/jbhi.2020.3027680] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Long noncoding RNAs (lncRNAs) have emerged as potential prognostic markers in various human cancers as they participate in many malignant behaviors. However, the value of lncRNAs as prognostic markers among diverse human cancers is still under investigation, and a systematic signature based on these transcripts that related to pan-cancer prognosis has yet to be reported. In this study, we proposed a framework to incorporate statistical power, biological rationale, and machine learning models for pan-cancer prognosis analysis. The framework identified a 5-lncRNA signature (ENSG00000206567, PCAT29, ENSG00000257989, LOC388282, and LINC00339) from TCGA training studies (n = 1,878). The identified lncRNAs are significantly associated (all P ≤ 1.48E-11) with overall survival (OS) of the TCGA cohort (n = 4,231). The signature stratified the cohort into low- and high-risk groups with significantly distinct survival outcomes (median OS of 9.84 years versus 4.37 years, log-rank P = 1.48E-38) and achieved a time-dependent ROC/AUC of 0.66 at 5 years. After routine clinical factors involved, the signature demonstrated better performance for long-term prognostic estimation (AUC of 0.72). Moreover, the signature was further evaluated on two independent external cohorts (TARGET, n = 1,122; CPTAC, n = 391; National Cancer Institute) which yielded similar prognostic values (AUC of 0.60 and 0.75; log-rank P = 8.6E-09 and P = 2.7E-06). An indexing system was developed to map the 5-lncRNA signature to prognoses of pan-cancer patients. In silico functional analysis indicated that the lncRNAs are associated with common biological processes driving human cancers. The five lncRNAs, especially ENSG00000206567, ENSG00000257989 and LOC388282 that never reported before, may serve as viable molecular targets common among diverse cancers.
Collapse
|
|
7
|
Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs. Cancers (Basel) 2021; 13:cancers13071674. [PMID: 33918136 PMCID: PMC8037840 DOI: 10.3390/cancers13071674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary This review provides a critical overview of the state of the art of the characterization of the immunological profile of a rare component of the tumors, denominated cancer stem cells (CSCs) or cancer initiating cells (CICs). These cells are endowed with the ability to form and propagate tumors and resistance to therapies, including the most innovative approaches. These investigations contribute to understanding the mechanisms regulating the interaction of CSCs/CICs with the immune system and identifying novel therapeutic approaches to render these cells visible and susceptible to immune responses. Abstract Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.
Collapse
|
|
8
|
Uddin MS, Mamun AA, Alghamdi BS, Tewari D, Jeandet P, Sarwar MS, Ashraf GM. Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Semin Cancer Biol 2020; 83:100-120. [PMID: 33370605 DOI: 10.1016/j.semcancer.2020.12.015] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common form of brain cancer and one of the most aggressive cancers found in humans. Most of the signs and symptoms of GBM can be mild and slowly aggravated, although other symptoms might demonstrate it as an acute ailment. However, the precise mechanisms of the development of GBM remain unknown. Due to the improvement of molecular pathology, current researches have reported that glioma progression is strongly connected with different types of epigenetic phenomena, such as histone modifications, DNA methylation, chromatin remodeling, and aberrant microRNA. Furthermore, the genes and the proteins that control these alterations have become novel targets for treating glioma because of the reversibility of epigenetic modifications. In some cases, gene mutations including P16, TP53, and EGFR, have been observed in GBM. In contrast, monosomies, including removals of chromosome 10, particularly q23 and q25-26, are considered the standard markers for determining the development and aggressiveness of GBM. Recently, amid the epigenetic therapies, histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors have been used for treating tumors, either single or combined. Specifically, HDACIs are served as a good choice and deliver a novel pathway to treat GBM. In this review, we focus on the epigenetics of GBM and the consequence of its mutations. We also highlight various treatment approaches, namely gene editing, epigenetic drugs, and microRNAs to combat GBM.
Collapse
Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Abdullah Al Mamun
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong Special Administrative Region
| | - Badrah S Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Devesh Tewari
- Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, PO Box 1039, 51687, Reims Cedex 2, France
| | - Md Shahid Sarwar
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali-3814, Bangladesh
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| |
Collapse
|
|
9
|
Ji Y, Yu C, Zhang H. contamDE-lm: linear model-based differential gene expression analysis using next-generation RNA-seq data from contaminated tumor samples. Bioinformatics 2020; 36:2492-2499. [PMID: 31917401 DOI: 10.1093/bioinformatics/btaa006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/30/2019] [Accepted: 01/03/2020] [Indexed: 11/14/2022] Open
Abstract
MOTIVATION Tumor and adjacent normal RNA samples are commonly used to screen differentially expressed genes between normal and tumor samples or among tumor subtypes. Such paired-sample design could avoid numerous confounders in differential expression (DE) analysis, but the cellular contamination of tumor samples can be an important noise and confounding factor, which can both inflate false-positive rate and deflate true-positive rate. The existing DE tools that use next-generation RNA-seq data either do not account for cellular contamination or are computationally extensive with increasingly large sample size. RESULTS A novel linear model was proposed to avoid the problem that could arise from tumor-normal correlation for paired samples. A statistically robust and computationally very fast DE analysis procedure, contamDE-lm, was developed based on the novel model to account for cellular contamination, boosting DE analysis power through the reduction in individual residual variances using gene-wise information. The desired advantages of contamDE-lm over some state-of-the-art methods (limma and DESeq2) were evaluated through the applications to simulated data, TCGA database and Gene Expression Omnibus (GEO) database. AVAILABILITY AND IMPLEMENTATION The proposed method contamDE-lm was implemented in an updated R package contamDE (version 2.0), which is freely available at https://github.com/zhanghfd/contamDE. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Yifan Ji
- Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China
| | - Chang Yu
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China
| | - Hong Zhang
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China
| |
Collapse
|
|
10
|
Kavari SL, Shah K. Engineered stem cells targeting multiple cell surface receptors in tumors. Stem Cells 2020; 38:34-44. [PMID: 31381835 PMCID: PMC6981034 DOI: 10.1002/stem.3069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 12/15/2022]
Abstract
Multiple stem cell types exhibit inherent tropism for cancer, and engineered stem cells have been used as therapeutic agents to specifically target cancer cells. Recently, stem cells have been engineered to target multiple surface receptors on tumor cells, as well as endothelial and immune cells in the tumor microenvironment. In this review, we discuss the rationales and strategies for developing multiple receptor-targeted stem cells, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics.
Collapse
Affiliation(s)
- Sanam L Kavari
- Center for Stem Cell Therapeutics and Imaging (CSTI), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging (CSTI), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
| |
Collapse
|
|
11
|
Asrij/OCIAD1 suppresses CSN5-mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence. Blood 2019; 133:2385-2400. [PMID: 30952670 DOI: 10.1182/blood.2019000530] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/18/2019] [Indexed: 12/11/2022] Open
Abstract
Inactivation of the tumor suppressor p53 is essential for unrestrained growth of cancers. However, only 11% of hematological malignancies have mutant p53. Mechanisms that cause wild-type p53 dysfunction and promote leukemia are inadequately deciphered. The stem cell protein Asrij/OCIAD1 is misexpressed in several human hematological malignancies and implicated in the p53 pathway and DNA damage response. However, Asrij function in vertebrate hematopoiesis remains unknown. We generated the first asrij null (knockout [KO]) mice and show that they are viable and fertile with no gross abnormalities. However, by 6 months, they exhibit increased peripheral blood cell counts, splenomegaly, and an expansion of bone marrow hematopoietic stem cells (HSCs) with higher myeloid output. HSCs lacking Asrij are less quiescent and more proliferative with higher repopulation potential as observed from serial transplantation studies. However, stressing KO mice with sublethal γ irradiation or multiple injections of 5-fluorouracil results in reduced survival and rapid depletion of hematopoietic stem/progenitor cells (HSPCs) by driving them into proliferative exhaustion. Molecular and biochemical analyses revealed increased polyubiquitinated protein levels, Akt/STAT5 activation and COP9 signalosome subunit 5 (CSN5)-mediated p53 ubiquitination, and degradation in KO HSPCs. Further, we show that Asrij sequesters CSN5 via its conserved OCIA domain, thereby preventing p53 degradation. In agreement, Nutlin-3 treatment of KO mice restored p53 levels and reduced high HSPC frequencies. Thus, we provide a new mouse model resembling myeloproliferative disease and identify a posttranslational regulator of wild-type p53 essential for maintaining HSC quiescence that could be a potential target for pharmacological intervention.
Collapse
|
|
12
|
MISTRG mice support engraftment and assessment of nonhuman primate hematopoietic stem and progenitor cells. Exp Hematol 2018; 70:31-41.e1. [PMID: 30590092 DOI: 10.1016/j.exphem.2018.12.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/20/2022]
Abstract
Preclinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large-animal models such as nonhuman primates (NHPs). Here, we wished to determine whether mouse models would allow engraftment of NHP HSPCs, which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells (HSPCs). No engraftment of NHP HSPCs was observed in NSG mice, whereas the gene-humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus. Most importantly, and closely mimicking the hematopoietic recovery of autologous stem cell transplantations in the NHP, only HSC-enriched CD34+CD90+CD45RA- cell fractions engrafted and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first "monkeynized" mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. The availability of this model has the potential to pre-evaluate novel HSC-mediated gene therapy approaches, inform studies in the NHP, and improve the overall outcome of large-animal experiments.
Collapse
|