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Mechanistically, we demonstrate that <jats:italic>DYRK1A<\/jats:italic> is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human <jats:italic>KMT2A<\/jats:italic>-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing <jats:italic>KMT2A<\/jats:italic>-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased <jats:italic>KMT2A<\/jats:italic>-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in <jats:italic>KMT2A<\/jats:italic>-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.<\/jats:p>","DOI":"10.1038\/s41375-025-02575-w","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T01:25:40Z","timestamp":1743125140000},"page":"1078-1089","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-2588","authenticated-orcid":false,"given":"V. S. S. 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TAM is a paid consultant for and shareholder in Dark Blue Therapeutics Ltd. SKT receives research funding from Incyte Corporation and Kura Oncology, serves\/d on scientific advisory boards for Aleta Biotherapeutics, AstraZeneca, Jazz Pharmaceuticals, Kura Oncology, Syndax Pharmaceuticals, and Wugen, Inc., and has received travel support from Amgen and Jazz Pharmaceuticals (all for unrelated studies).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. We have complied with all the relevant ethical regulations for animal testing and research. All animal-related experiments have received ethical approval from Loma Linda University Institutional Animal Care and Use Committee (IACUC-23-029).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}