Co‐operative epigenetic remodelling by Setd2 deficiency and Kras mutation drives juvenile myelomonocytic leukaemia development and MEK inhibitor sensitivity

Summary Juvenile myelomonocytic leukaemia (JMML) primarily stems from the Rat Sarcoma (RAS)/Extracellular Signal‐Regulated Kinase (ERK) pathway mutations, and currently, there are no effective regimens against JMML, yet various studies have highlighted the importance of deciphering secondary genetic and/or epigenetic alterations in pursuit of treatments. Setd2 ‐mediated‐H3K36me3 participates in myriad biological functions and primarily serves as a tumour suppressor gene in carcinogenesis. However, little is known about the synergism between Setd2 deficiency and Kras mutation during JMML onset and progression. Herein, we reveal that Kras ‐mutant JMML possesses a lower H3K36 trimethylation mark, and Setd2 ablation in the KrasG12D/+‐mediated JMML model shortens the disease latency. Phenotypically, Setd2 deficiency perturbs myeloid progenitor cell differentiation in KrasG12D/+ mutant mice and confers enhanced proliferative ability. Furthermore, the functional studies demonstrate that concurrent Setd2 depletion and Kras mutation expression promote cell cycle progression and enhance colony‐forming ability while escaping apoptosis. Mechanistically, myeloid progenitor cells derived from Setd2−/−; KrasG12D/+ co‐mutant mice hyperactivate ERK1/2 by reducing the H3K36me3 level on the Dusp1 gene body. Interestingly, a combination of mitogen‐activated protein kinase (MEK) and Setd2 inhibitors effectively inhibits the malignant growth of human and mouse leukaemia cell lines in vitro. Hence, the current project provides strong concepts for targeting ERK signalling and Setd2 in oncogenic RAS‐mediated leukaemia.