Bet Inhibitor-Based Combinations Targeting Novel Dependencies in MECOM-Rearranged (R) AML

Authors

Christine E Birdwell
Warren Fiskus
Christopher P Mill
Tapan M Kadia
Naval Daver
Courtney D DiNardo
Koji Sasaki
John A Davis
Kaberi Das
Hanxi Hou
Antrix Jain
Anna Malovannaya
Lauren B Flores
Rasoul Pourebrahim
Selina Yuan
Xiaoping Su
Michele Ceribelli
Kapil N Bhalla

Language

English

Publication Date

2-1-2026

Journal

Leukemia

DOI

10.1038/s41375-025-02842-w

PMID

41419608

PMCID

PMC12875863

PubMedCentral® Posted Date

12-19-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Leukemia, Myeloid, Acute, Animals, Mice, MDS1 and EVI1 Complex Locus Protein, Transcription Factors, Xenograft Model Antitumor Assays, Gene Rearrangement, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Bromodomain Containing Proteins, Imidazoles, Quinolines, Cell Cycle Proteins

Published Open-Access

yes

Recommended Citation

Birdwell, Christine E; Fiskus, Warren; Mill, Christopher P; et al., "Bet Inhibitor-Based Combinations Targeting Novel Dependencies in MECOM-Rearranged (R) AML" (2026). Faculty, Staff and Student Publications. 5551.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5551