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Therapeutic Potential of Enhancing p300 Catalytic Activity in MDS/AML

By: Kayci Reyer
Posted: Friday, November 19, 2021

The activation of acetyltransferase p300 may result in tumor suppression in patients with acute myeloid leukemia (AML) who have myelodysplastic syndromes (MDS) and deficient TET2 function, according to molecular research presented in JCI Insight. Stephen D. Nimer, MD, of the University of Miami Miller School of Medicine, and colleagues found that, conversely, hematopoietic stem cell and progenitor cell (HSPC) malignancies thrived when p300 was inhibited. Dr. Nimer and his co-investigators emphasized the potential therapeutic application of p300 activators in the treatment of patients with MDS who have TET2-inactivating mutations.

According to the researchers, MDS are driven by epigenetic regulators TET2, ASXL1, and SRSF2. In primary and transplantation mouse models, Tet2-deficient HSPCs had greater capacity for proliferation and self-renewal following the loss of p300. This led to increased leukemogenicity, a larger HSPC pool, and modified gene expression related to differentiation, proliferation, and leukemia development. An inverse association was noted between p300 and Myb expression; Myb decreased when p300 was enhanced. Lower Myb expression hampered HSPC proliferation, the researchers explained, and led to improved survival in mouse models. When p300 expression was inhibited, Ep300 deletion was phenocopied in Tet2-deficient HSPCs. However, when p300 expression was increased, Tet2-deficient cells became less capable of self-renewing and experienced impaired leukemogenicity.

The study authors concluded: “We found that the loss of p300 or its chemical inhibition induced (a) a profound reprogramming of the epigenome and transcriptome of premalignant HSPCs, leading to impaired differentiation and signal transduction; (b) a unique gene-expression signature in Tet2-null HSPCs, related to enhanced proliferation and oncogenicity; (c) an increase in Myb expression, which directly amplifies malignant transformation of MDS HSPCs; (d) an accelerated disease progression in multiple MDS models.”

Disclosure: For full disclosures of the study authors, visit insight.jci.org.



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