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The DNA damage response (DDR) and DOT1L\/H3K79me pathways are required to maintain LSCs in <jats:italic>MLLr<\/jats:italic>-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in <jats:italic>MLLr<\/jats:italic>-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in <jats:italic>MLLr<\/jats:italic>-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in <jats:italic>MLLr<\/jats:italic>-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in <jats:italic>MLLr<\/jats:italic>-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.<\/jats:p>","DOI":"10.1038\/s41388-024-02998-2","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T06:02:11Z","timestamp":1714111331000},"page":"1900-1916","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The DNA damage-independent ATM signalling maintains CBP\/DOT1L axis in MLL rearranged acute myeloid leukaemia"],"prefix":"10.1038","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3402-1443","authenticated-orcid":false,"given":"Guangming","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyong","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyuan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junke","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8230-0335","authenticated-orcid":false,"given":"Bing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8565-1723","authenticated-orcid":false,"given":"Jun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-1987","authenticated-orcid":false,"given":"Aibin","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"2998_CR1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1182\/blood-2009-03-209262","volume":"114","author":"JW Vardiman","year":"2009","unstructured":"Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. 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