BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

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Publication Details

Journal
Leukemia
Published
2025-12-19
DOI
https://doi.org/10.1038/s41375-025-02842-w
Citations
1
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.81

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article

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML

Christine Birdwell, Courtney Denton Dinardo, Rasoul Pourebrahim, Anna Malovannaya et al.
1 citations
Leukemia
Protein Degradation and Inhibitors
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article

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML

Christine Birdwell, Courtney Denton Dinardo, Rasoul Pourebrahim, Anna Malovannaya, Christopher P. Mill, Lauren B. Flores, Tapan Mahendra Kadia, Antrix Jain, Koji Sasaki, Naval Guastad Daver, Michele Ceribelli, Shuanghu Yuan, Warren C. Fiskus, Xiaoping Su, Kaberi Das, Hanxi Hou, Kapil N. Bhalla, John A. Davis
article en
1 citations

Abstract

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

LeukemiaVol. 40(2)
National Institutes of Health (US), University of St. Thomas - Texas (US), The University of Texas MD Anderson Cancer Center (US), Baylor College of Medicine (US), St. Luke's Episcopal Hospital (US), St. Ann's Episcopal Church (US), National Center for Advancing Translational Sciences (US)
Cancer Prevention and Research Institute of Texas, National Institutes of Health, University of Texas MD Anderson Cancer Center
Openalex Percentile: Top 21%
Protein Degradation and Inhibitors
0.81
DOIOpen Access PDFOpenAlex
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