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However, little is known about the synergism between\n                    <jats:italic>Setd2<\/jats:italic>\n                    deficiency and\n                    <jats:italic>Kras<\/jats:italic>\n                    mutation during JMML onset and progression. Herein, we reveal that\n                    <jats:italic>Kras<\/jats:italic>\n                    \u2010mutant JMML possesses a lower H3K36 trimethylation mark, and\n                    <jats:italic>Setd2<\/jats:italic>\n                    ablation in the KrasG12D\/+\u2010mediated 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\u2010forming ability while escaping apoptosis. Mechanistically, myeloid progenitor cells derived from\n                    <jats:italic>Setd2\u2212\/\u2212; KrasG12D\/+<\/jats:italic>\n                    co\u2010mutant mice hyperactivate ERK1\/2 by reducing the H3K36me3 level on the\n                    <jats:italic>Dusp1<\/jats:italic>\n                    gene body. Interestingly, a combination of mitogen\u2010activated protein kinase (MEK) and Setd2 inhibitors effectively inhibits the malignant growth of human and mouse leukaemia cell lines in\u00a0vitro. Hence, the current project provides strong concepts for targeting ERK signalling and Setd2 in oncogenic RAS\u2010mediated leukaemia.\n                  <\/jats:p>","DOI":"10.1111\/bjh.70060","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:19:11Z","timestamp":1754299151000},"page":"1289-1300","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Co\u2010operative epigenetic remodelling by\n                    <i>Setd2<\/i>\n                    deficiency and\n                    <i>Kras<\/i>\n                    mutation drives juvenile myelomonocytic leukaemia development and\n                    <scp>MEK<\/scp>\n                    inhibitor sensitivity"],"prefix":"10.1111","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6552-8944","authenticated-orcid":false,"given":"Gustave","family":"Munyurangabo","sequence":"first","affiliation":[{"name":"Department of Haematology, National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2918-3224","authenticated-orcid":false,"given":"Linlin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Haematology, National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an Shaanxi People's Republic of China"},{"name":"Center for Tumor and Immunology, The Precision Medical Institute Xi'an Jiaotong University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Haematology, National &amp; Local Joint Engineering Research Center of 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University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Haematology, National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Medical Technology Xi'an Medical University  Shaanxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-0016","authenticated-orcid":false,"given":"Guangyao","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Haematology, National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of 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