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P300 suppresses the transition of myelodysplastic syndrome to acute myeloid leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE145878 | GEO | 2021/11/03

REPOSITORIES: GEO

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p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia.

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

| S-EPMC8525640 | biostudies-literature

p300 suppresses the transition of myelodysplastic syndrome to acute myeloid leukemia [DIP-seq]

Project description:The p300 lysine acetyltransferase (KAT) can function as an oncogene or a tumor suppressor in hematologic malignancies. We have identified a tumor suppressor role for p300 in myelodysplastic syndrome (MDS) driven by Tet2 deficiency. Compared to Tet2-null hematopoietic stem and progenitor cells (HSPCs), HSPCs lacking both p300 and Tet2 (double knock out, DKO) displayed enhanced proliferation and impaired differentiation. Consequently, p300Δ/Δ Tet2-/- mice developed acute myeloid leukemia. p300 loss in Tet2-/- HSPCs induced a global epigenomic reprogramming that enhanced leukemogenicity at least in part by increasing expression of Myb, as knock-down of Myb specifically hindered the proliferation of the DKO HSPCs. We show that p300 KAT activity regulates the function of Tet2 null HSPCs, and that augmenting p300 function impairs their unlimited self-renewal. Such a strategy could prove useful in individuals with Tet2 deficient hematopoiesis or MDS.

2021-11-03 | GSE145877 | GEO