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<p>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&#xa0;further evaluation of these BETi-based combinations.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • 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

摘要

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.