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.
Fiskus et al. (Thu,) studied this question.
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