A PRC2-Kdm5b axis sustains tumorigenicity of acute myeloid leukemia
Zhihong Ren, Arum Kim, Yu‐Ting Huang, Wen‐Chieh Pi, Weida Gong, Xufen Yu, Jun Qi, Jian Jin, Ling Cai, Robert G. Roeder, Wei‐Yi Chen, Gang Greg Wang
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.