p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia
Autor: | Feng Chun Yang, Philip A. Cole, Qin Yang, Chuan Chen, Beth E. Zucconi, Fan Liu, Stephen D. Nimer, Concepción Martínez, Shi Chen, Stephanie Duffort, Ye Xu, Pierre-Jacques Hamard, Luisa Cimmino, Na Man, Jun Sun, Daniel L. Karl, Maria E. Figueroa, Miguel Torres-Martin, Hidehiro Itonaga, Gloria Mas, Mingjiang Xu |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Biology
Dioxygenases Epigenesis Genetic Mice Proto-Oncogene Proteins c-myb hemic and lymphatic diseases Leukemias medicine Animals MYB p300-CBP Transcription Factors Progenitor cell EP300 Cell Proliferation Serine-Arginine Splicing Factors Myelodysplastic syndromes Myeloid leukemia Cell Differentiation General Medicine Hematology medicine.disease Hematopoietic Stem Cells Transplantation DNA-Binding Proteins Repressor Proteins Survival Rate Haematopoiesis Leukemia Disease Models Animal Leukemia Myeloid Acute Myelodysplastic Syndromes Mutation Cancer research Disease Progression Epigenetics Research Article |
Zdroj: | JCI Insight |
ISSN: | 2379-3708 |
Popis: | 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. |
Databáze: | OpenAIRE |
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