Abstract
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.
Highlights
Normal hematopoiesis is a process that involves the coordination of stem and progenitor cell self-renewal and differentiation
The flow cytometry data confirmed that the loss of p300 increased the frequencies of c-Kit+ cells and lineage– Sca1+c-Kit+ (LSK) cells in the bone marrow (Figure 1, E–G); we found an increased percentage of myeloid cells (Mac1+; Figure 1H) and a decreased percentage of B cells (B220+; Figure 1I)
In Tet2-deficient mice, the loss of p300 promoted the proliferation of hematopoietic stem and progenitor cell (HSPC) with myeloid skewing, resulting in an increased HSPC pool in the bone marrow and accelerated disease progression in vivo
Summary
Normal hematopoiesis is a process that involves the coordination of stem and progenitor cell self-renewal and differentiation. Somatic and germline mutations in MDS patients affect genes encoding DNA methylation regulators (TET2 and DNMT3A), chromatin modifiers (ASXL1 and EZH2), splicing factors (SRSF2, U2AF1, and SF3B1), TFs (EVI1, RUNX1, and GATA2), and signaling pathway intermediates [3]. Among these mutations, TET2 inactivating mutations are found in approximately 20% of MDS patients but are seen in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms [4,5,6,7]. The loss of Tet in hematopoietic cells leads to a global loss of 5-hmC and hematopoietic defects, including enhanced hematopoietic stem cell (HSC) self-renewal, myeloid cell expansion, and an increased propensity to develop MDS or acute leukemia [8,9,10,11,12,13]
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