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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1+ AML, whereas transcriptomic analysis reveal that Kdm5b, a lysine demethylase gene carrying “bivalent” chromatin domains, is directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion not only promoted tumorigenicity but also attenuated anti-AML effects of PRC2 inhibitors, demonstrating a PRC2–jKdm5b axis for AML oncogenesis. Integrated RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling also showed that Kdm5b directly binds and represses AML stemness genes. The anti-AML effect of Kdm5b relies on its chromatin association and/or scaffold functions rather than its demethylase activity. Collectively, this study describes a molecular axis that involves histone modifiers (PRC2–jKdm5b) for sustaining AML oncogenesis.

Original languageEnglish
Article numbere2122940119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - 1 Mar 2022


  • AML
  • Kdm5b
  • PRC2
  • Stemness
  • Tumorigenicity


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