Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

Wei, Yiping; Cao, Yanjia; Sun, Rui; Cheng, Lin; Xiong, Xia; Jin, Xin; He, Xiaohua; Lu, Wenyi; Zhao, Mingfeng

doi:10.3389/fonc.2020.584974

Cited by 51 publications

(39 citation statements)

References 118 publications

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“…MYC is one of the most prevalent human oncogenes, while HOXA9 is a common driver of leukemia (75,93,94,119). BCL2 is the target of venetoclax, one of the most promising novel therapies for AML (85). Our study clarifies the complex reported interactions between IRF8, HOXA9 and MEF2C/D proteins.…”

Section: Dynamic Behaviors Of Tf and Mediator Punctasupporting

confidence: 57%

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A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Harada

Heshmati

Kalfon

et al. 2021

Preprint

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A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.

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Section: Dynamic Behaviors Of Tf and Mediator Punctasupporting

confidence: 57%

“…We conclude that IRF8 directly activates transcription of MEF2D, while direct targets of MEF2D include key leukemogenic TFs HOXA9 and MYC (Figure 7H). Direct targets of both TFs include other essential genes, including IRF8 regulation of BCL2, an important therapeutic target in AML (85).…”

Section: The Irf8/mef2 Axis Regulates Key Oncogenes In Kmt2ar Amlmentioning

confidence: 99%

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Harada

Heshmati

Kalfon

et al. 2021

Preprint

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“…However, only 20% of the cells were dead after 72 h of treatment, showing a modest efficacy. Multiple studies previously reported cancer cells’ adaptation to therapy and the key role of the anti-apoptotic BCL-2 family proteins in their resistance to cell death ( Reed et al, 1996 ; Mansoori et al, 2017 ; Maji et al, 2018 ; Wei et al, 2020 ). We next sought to study the role of these proteins after trametinib treatment on NALM-6.…”

Section: Resultsmentioning

confidence: 99%

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Manzano-Muñoz

Alcon

Menéndez

et al. 2021

Front. Cell Dev. Biol.

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Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 – a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.

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“…It binds and sequesters the pro-apoptotic Bax/Bak proteins and, thus, prevents the release of cytochrome c [98]. Overexpression of the anti-apoptotic factors Mcl-1, Bcl-2 and Bcl-xL in acute myeloid leukaemia [99] and acute lymphocytic leukaemia [100] may be associated dysregulation of apoptosis. The level of the anti-apoptotic protein Mcl-1 was downregulated in a dose-dependent manner after treating MCF-7 cells with compound 10n (0.05, 0.1 and 0.5 μM) for 48 or 72 h. (Figure 10).…”

Section: Effects Of Compound 10n On Tubulin Polymerisation In Mcf-7 Cellsmentioning

confidence: 99%

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

et al. 2021

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Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

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Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

Cited by 51 publications

References 118 publications

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

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