Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia

摘要: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in differentiation and increased proliferation neoplastic precursor cells. Outcomes for patients with AML remain poor, highlighting the need novel treatment options. Aberrant epigenetic regulation plays an important role pathogenesis AML, inhibitors DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity preclinical models. Combination studies HDAC plus potential beneficial clinical however toxicity profiles non-selective combination setting limit their utility. In this work, we describe development selective HDAC1 HDAC2, which are hypothesized to improved safety profiles, therapy AML. We demonstrate that inhibition HDAC2 sufficient achieve efficacy both as single agent azacitidine models including established lines, primary cells from patient bone marrow samples vivo xenograft human Gene expression profiling treated either HDAC1/2 inhibitor, azacitidine, identified list genes involved transcription cycle mediators combinatorial effects azacitidine. Together, these findings support evaluation patients.