p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia

• DOI: 10.1172/jci.insight.138478
• Publication Date: 2021-10-07T18:02:20Z
• Authors: Na Man; Gloria Mas; Daniel L. Karl; Jun Sun; Fan Liu; Qin Yang; Miguel Torres-Martin; Hidehiro Itonaga; Concepcion Martinez; Shi Chen; Ye Xu; Stephanie Duffort; Pierre-Jacques Ha...; Chuan Chen; Beth E. Zucconi; Luisa Cimmino; Feng-Chun Yang; Mingjiang Xu; Philip A. Cole; Maria E. Figueroa; Stephen D. Nimer
• Keywords: Histone acetyltransferase

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis an increased risk of leukemia transformation. Epigenetic regulators recurrently mutated in MDS, directly implicating epigenetic dysregulation MDS pathogenesis. Here, we identified a tumor suppressor role the acetyltransferase p300 clinically relevant models driven mutations TET2, ASXL1, SRSF2. The loss enhanced proliferation self-renewal capacity Tet2-deficient HSPCs, resulting HSPC pool leukemogenicity primary transplantation mouse models. Mechanistically, HSPCs altered enhancer accessibility expression genes associated with differentiation, proliferation, development. Particularly, led to Myb, depletion Myb attenuated improved survival leukemia-bearing mice. Additionally, show that chemical inhibition activity phenocopied Ep300 deletion whereas activation small molecule impaired cells. This suggests potential therapeutic application activators treatment TET2 inactivating mutations.