• AML
• Apoptosis
• Cytarabine
• Homoharringtonine
• p38 MAPK

• Humans
• Homoharringtonine/pharmacology
• Cytarabine/pharmacology
• Myeloid Cell Leukemia Sequence 1 Protein/metabolism
• Leukemia, Myeloid, Acute/drug therapy
• Leukemia, Myeloid, Acute/metabolism
• Leukemia, Myeloid, Acute/pathology
• Leukemia, Myeloid, Acute/genetics
• Apoptosis/drug effects
• p38 Mitogen-Activated Protein Kinases/metabolism
• Animals
• Mice
• Xenograft Model Antitumor Assays
• Histones/metabolism
• Cell Line, Tumor
• Drug Synergism
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Phosphorylation/drug effects
• Female

• AKT/GSK3β/CREB axis
• Cytarabine
• HuR axis
• Leukemia
• MCL1 downregulation
• p38 MAPK

• DNA damage
• XPO1 inhibitor
• acute myeloid leukaemia
• combination treatment
• venetoclax

• Antineoplastic Agents/pharmacology
• Apoptosis
• Bridged Bicyclo Compounds, Heterocyclic
• Cell Line, Tumor
• DNA Damage
• Humans
• Karyopherins
• Leukemia, Myeloid, Acute/genetics
• Receptors, Cytoplasmic and Nuclear
• Sulfonamides
• Exportin 1 Protein

• 81800154 National Natural Science Foundation of China
• National Natural Science Foundation of China

• BCL-2
• BCL-XL
• BH3-mimetics
• MCL-1
• apoptosis

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Drug Delivery Systems
• Drug Discovery
• Humans
• Ligands
• Molecular Mimicry
• Proto-Oncogene Proteins c-bcl-2/drug effects

BCL-X is a member of the BCL-2 family. It regulates apoptosis and plays a critical role in hematological malignancies. It is well-known that >90% of human genes undergo alternative splicing. A total of 10 distinct splicing transcripts of the BCL-X gene have been identified, including transcript variants 1–9 and ABALON. Different transcripts from the same gene have different functions. The present review discusses the progress in understanding the different alternative splicing transcripts of BCL-X, including their characteristics, functions and expression patterns. The potential use of BCL-X in targeted therapies for hematological malignancies is also discussed.

• BCL-X
• alternative splicing
• hematological malignancies

•

Obatoclax, the Bcl-2 inhibitor directly impaired HCC cell growth.

Bcl-2 family proteins play critical roles in regulating lymphocyte development and maintain homeostasis, and have also been proved to be involved in various cancer types development. However, the role of Bcl-2 in hepatocellular carcinoma (HCC) development has not been clearly studied. Here, we reported the pan-Bcl-2 inhibitor, obatoclax could directly inhibit HCC growth in vitro. We further demonstrated in murine HCC model that obatoclax also suppressed HCC development in vivo. We also proved that although obatoclax inhibited T cells expansion, it had no influence on T cells activation in vivo. Mechanism study revealed that obatoclax sensitized HCC cells to T cell-mediated killing. Combination therapy of obatoclax with anti-PD-1 antibody synergistically suppressed HCC development and prolonged the survival rate of tumor-bearing mice. The combination therapy promoted T cells activation and effector cytokines expression both in spleen and tumor. In summary, our results proved that obatoclax sensitized HCC cells to T cell -mediated killing. Combination of obatoclax with immune checkpoint blockade served as a promising therapeutic strategy for HCC treatment.

• Bcl-2
• HCC
• Immune checkpoint blockade
• Obatoclax

• targeted therapies
• acute myeloid leukaemia
• chronic myeloid leukaemia

• Animals
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Bridged Bicyclo Compounds, Heterocyclic/adverse effects
• Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
• Drug Design
• Humans
• Leukemia, Myeloid/drug therapy
• Leukemia, Myeloid/metabolism
• Leukemia, Myeloid/pathology
• Molecular Mimicry
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Signal Transduction
• Sulfonamides/adverse effects
• Sulfonamides/therapeutic use

• Wellcome Trust
• 204820/Z/16/Z Wellcome Trust
• University of Glasgow
• Wellcome Trust (Wellcome)
• Novartis
• Bristol-Myers Squibb (Bristol-Myers Squibb Company)
• Takeda Pharmaceutical Company (Takeda Pharmaceutical Company Limited)
• Cyclacel Pharmaceuticals Inc., Berkeley Heights, New Jersey, United States

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

• Acute myeloid leukemia
• Compound K
• Cytarabine
• Cytidine deaminase
• Deoxycytidine kinase

MLAA-34 is a novel leukemia-associated gene closely related to the carcinogenesis of acute monocytic leukemia (AML). MLAA-34 over expression has been observed to inhibit apoptosis in vitro. JAK2/STAT3 pathway plays an important role in cell proliferation, differentiation and inhibition of apoptosis in number of cancers. However, the relationship and interaction between MLAA-34 and JAK2/STAT3 has never been investigated in AML.

This study investigates and reports a novel relationship between MLAA-34 and JAK2/STAT3 pathway in AML both in vitro and in vivo. We constructed MLAA-34 knockdown vector and transfected U937 cells to observe its apoptotic activities in relation to JAK2/STAT3 signaling pathway in vitro and then in vivo in mouse model. Levels of expression of MLAA-34 and JAK2/STAT3 and its downstream targets were also measured in AML patients and a few volunteers.

We found that MLAA-34 knockdown increased U937 apoptosis in vitro and inhibited tumor growth in vivo. Components of the canonical JAK2/STAT3 pathway or its downstream targets, including c-myc, bcl-2, Bax, and caspase-3, were shown to be involved in the carcinogenesis of AML. We also found that the JAK2/STAT3 pathway positively regulated MLAA-34 expression. We additionally identified a STAT3 binding site in the MLAA-34 promoter where STAT3 binds directly and activates MLAA-34 expression. In addition, MLAA-34 was found to form a complex with JAK2 and was enhanced by JAK2 activation. Correlation of MLAA-34 and JAK2/STAT3 was further confirmed in AML patients.

In conclusion, MLAA-34 is a novel regulator for JAK2/STAT3 signaling, and in turn, is regulated by this interaction in a positive feedback loop. Thus we report a novel model of interaction mechanism between MLAA-34 and JAK2/STAT3 which can be utilized as a potential target for a novel therapeutic approach in AML.

• JAK2/STAT3
• MLAA-34
• acute monocytic leukemia
• positive feedback loop

One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

• Acute myeloid leukemia
• Apoptosis
• Differentiation
• HL-60 cells
• Obatoclax

• colon cancer
• differential scanning fluorometry
• microRNA
• natural products
• pre-miR-21

Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML) in adult patients aged 75 years or older, or otherwise unable to tolerate intensive induction chemotherapy, in combination with either hypomethylating agents or low-dose cytarabine. In this review article, we discuss venetoclax’s mechanism of action, in relation to both the BCL-2 protein family in general and BH3-mimetic activity in particular. We then outline the pharmacological advances that preceded and facilitated its development, as well as providing an overview of key preclinical and clinical studies which lead to its use first in chronic lymphoid leukemia (CLL), then in small lymphocytic leukemia (SLL), and subsequently in AML. Finally, we seek to offer an overview of the challenges and opportunities encountered as venetoclax moves into more widespread use, including its use and activity against leukemia initiating cells and oxidative phosphorylation.

• ABT-199
• BCL-2 inhibitor
• BH3-mimetic
• acute myeloid leukemia
• apoptosis
• venetoclax

• ATR
• Acute myeloid leukemia
• Combination treatment
• DNA damage
• VE-822

Large-scale tumor genome sequencing projects have revealed a complex landscape of genomic mutations in multiple cancer types. A major goal of these projects is to characterize somatic mutations and discover cancer drivers, thereby providing important clues to uncover diagnostic or therapeutic targets for clinical treatment. However, distinguishing only a few somatic mutations from the majority of passenger mutations is still a major challenge facing the biological community. Fortunately, combining other functional features with mutations to predict cancer driver genes is an effective approach to solve the above problem. Protein lysine modifications are an important functional feature that regulates the development of cancer. Therefore, in this work, we have systematically analyzed somatic mutations on seven protein lysine modifications and identified several important drivers that are responsible for tumorigenesis. From published literature, we first collected more than 100,000 lysine modification sites for analysis. Another 1 million non-synonymous single nucleotide variants (SNVs) were then downloaded from TCGA and mapped to our collected lysine modification sites. To identify driver proteins that significantly altered lysine modifications, we further developed a hierarchical Bayesian model and applied the Markov Chain Monte Carlo (MCMC) method for testing. Strikingly, the coding sequences of 473 proteins were found to carry a higher mutation rate in lysine modification sites compared to other background regions. Hypergeometric tests also revealed that these gene products were enriched in known cancer drivers. Functional analysis suggested that mutations within the lysine modification regions possessed higher evolutionary conservation and deleteriousness. Furthermore, pathway enrichment showed that mutations on lysine modification sites mainly affected cancer related processes, such as cell cycle and RNA transport. Moreover, clinical studies also suggested that the driver proteins were significantly associated with patient survival, implying an opportunity to use lysine modifications as molecular markers in cancer diagnosis or treatment. By searching within protein-protein interaction networks using a random walk with restart (RWR) algorithm, we further identified a series of potential treatment agents and therapeutic targets for cancer related to lysine modifications. Collectively, this study reveals the functional importance of lysine modifications in cancer development and may benefit the discovery of novel mechanisms for cancer treatment.

• cancer
• clinical analysis
• lysine modifications
• pathway and network analysis
• somatic mutations

• Acute myeloid leukemia
• Bcl-2
• ERK
• PI3K
• mTOR

Acute myeloid leukemia (AML) is a serious disease. The 5-year survival rates remain frustratingly low (65% for children and 26% for adults). Resistance to frontline chemotherapy (usually cytarabine) often develops; therefore a new treatment modality is needed. Bcl-2 family proteins play an important role in balancing cell survival and apoptosis. The antiapoptotic Bcl-2 family proteins have been found to be dysregulated in AML. ABT-199, a BH3 mimetic, was developed to target antiapoptotic protein Bcl-2. Although ABT-199 has demonstrated promising results, resistance occurs. Previous studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2, but this is compensated by increased association of Bim with prosurvival protein Mcl-1, stabilizing Mcl-1, resulting in resistance to ABT-199. In this study, we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML cells. We found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient samples. The synergistic induction of apoptosis was decreased upon Bak, Bax and Bim knockdown. While A-1210477 treatment alone also increased Mcl-1 protein levels, combination with ABT-199 reduced binding of Bim to Mcl-1. Our results demonstrate that sequestration of Bim by Mcl-1, a mechanism of ABT-199 resistance, can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477.

• Drug resistance
• LY3009120.
• Obatoclax
• Thyroid cancer
• Vemurafenib

Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has described the antiproliferative action of obatoclax in one human colorectal cancer cell line without elucidating the underlying mechanisms. We herein reported that, in a panel of human colorectal cancer cell lines, obatoclax inhibits cell proliferation, suppresses clonogenicity, and induces G₁-phase cell cycle arrest, along with cyclin D1 downregulation. Notably, ectopic cyclin D1 overexpression abrogated clonogenicity suppression but also G₁-phase arrest elicited by obatoclax. Mechanistically, pre-treatment with the proteasome inhibitor MG-132 restored cyclin D1 levels in all obatoclax-treated cell lines. Cycloheximide chase analyses further revealed an evident reduction in the half-life of cyclin D1 protein by obatoclax, confirming that obatoclax downregulates cyclin D1 through induction of cyclin D1 proteasomal degradation. Lastly, threonine 286 phosphorylation of cyclin D1, which is essential for initiating cyclin D1 proteasomal degradation, was induced by obatoclax in one cell line but not others. Collectively, we reveal a novel anticancer mechanism of obatoclax by validating that obatoclax targets cyclin D1 for proteasomal degradation to downregulate cyclin D1 for inducing antiproliferation.

• BH3 (BCL-2 homology 3) mimetics
• G1-phase arrest
• antiproliferation
• colorectal cancer
• cyclin D1
• obatoclax
• proteasomal degradation

We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.

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.

• Leukemia stem cells
• Cancer stem cells
• Acute myeloid leukemia
• Stem cell niche
• Xenotransplantation
• Plerixafor
• NF-κB
• C-X-C chemokine receptor type 4

• ABT-737
• Anticancer agents
• Antileukemic activity
• BH3 mimetics
• Obatoclax

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Biphenyl Compounds/pharmacology
• Cell Line, Tumor
• Cell Survival/drug effects
• Flow Cytometry
• Humans
• Indoles
• Leukemia/pathology
• Nitrophenols/pharmacology
• Piperazines/pharmacology
• Pyrroles/pharmacology
• Sulfonamides/pharmacology

• Uniwersytet Jagielloński w Krakowie

• Acute myeloid leukemia
• Cytarabine
• DNA damage
• Drug combination
• Obatoclax