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Significance Acute myeloid leukemias (AMLs) with NUP98-NSD1 or MLL abnormality are generally aggressive, demanding a better understanding of the underlying oncogenic mechanisms. We show that these AMLs rely on a… Click to show full abstract
Significance Acute myeloid leukemias (AMLs) with NUP98-NSD1 or MLL abnormality are generally aggressive, demanding a better understanding of the underlying oncogenic mechanisms. We show that these AMLs rely on a regulatory axis involving PRC2–|Kdm5b–|stemness genes for sustaining an oncogenic program. The H3K27 methylase activity of polycomb repressive complex 2 (PRC2) is crucial for repressing Kdm5b, a corepressor carrying a H3K4me3 reader domain, that antagonizes the AML oncoproteins by directly binding to and down-regulating the AML stemness genes, thereby suppressing acute leukemogenesis. Such an AML-suppressing role of Kdm5b is not dependent on its intrinsic demethylase activity but requires its scaffold and/or chromatin association functions. The findings of this study shall aid in potential therapeutics of the affected AML patients.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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