Language
English
Publication Date
1-1-2026
Journal
Hemasphere
DOI
10.1002/hem3.70289
PMID
41551728
PMCID
PMC12806299
PubMedCentral® Posted Date
1-15-2026
PubMedCentral® Full Text Version
Post-print
Abstract
In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. EVI1 is a transcriptional regulator that plays a role in proliferation and maintenance of a stem cell-like phenotype in AML. BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive ATPases of the BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. They regulate access to enhancers/promoters and gene-expressions orchestrating AML stem/progenitor cell proliferation and differentiation. AML with 3q26.2 rearrangements are clinically challenging and prognosis remains very poor. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induced differentiation and lethality in AML cells with MECOM-r, perturbed chromatin accessibility and depleted expression of EVI1, c-Myc, CD44 and CDK4. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or HAT inhibitor synergistically induced in vitro lethality in patient-derived AML cells with MECOM-r. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.
Published Open-Access
yes
Recommended Citation
Fiskus, Warren; Mill, Christopher P; Piel, Jessica; et al., "Highly Effective Combination of BRG1/Brm Inhibitor With Bet Inhibitor or Decitabine for High-Risk MECOM-Rearranged AML" (2026). Faculty, Staff and Students Publications. 6468.
https://digitalcommons.library.tmc.edu/baylor_docs/6468