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Transl. Med."],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:p>\n                    Chemotherapy resistance in acute myeloid leukemia (AML) remains a major clinical challenge. Integration of multiomic profiling and in vivo functional genomics revealed splicing dysregulation as a determinant of chemoresistance in AML. We uncovered a network involving the splicing regulator SRRM1 and the CLK1\/4 and PAK1 kinase families as vulnerabilities in chemoresistant AML cells. Both kinase families are hyperactivated in chemoresistant cells, promoting SRRM1 phosphorylation and altering its scaffolding function. We also identified a relapse-associated\n                    <jats:italic toggle=\"yes\">PAK1<\/jats:italic>\n                    variant, c.1429G&gt;T p.(Ala\n                    <jats:sup>477<\/jats:sup>\n                    \u2192Ser), that confers chemotherapy resistance. Combined PAK1 and CLK1\/4 inhibition recapitulated the splicing changes induced by\n                    <jats:italic toggle=\"yes\">SRRM1<\/jats:italic>\n                    loss, preferentially targeting chemoresistant AML and enhancing chemotherapy efficacy in cell lines, primary cells, and mouse models. Last, we pinpointed MAP2K5 as a critical downstream effector because missplicing of exons 17 and 18 of\n                    <jats:italic toggle=\"yes\">MAP2K5<\/jats:italic>\n                    upon SRRM1 depletion sensitized cells to chemotherapy. Our findings highlight a therapeutic strategy to overcome AML relapse by targeting splicing dysregulation.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adx3847","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:58:12Z","timestamp":1783533492000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Splicing-associated network PAK1-CLK1\/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6960-3297","authenticated-orcid":true,"given":"Camille","family":"Vaganay","sequence":"first","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Ling","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2950-3089","authenticated-orcid":true,"given":"Lois M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6278-2105","authenticated-orcid":true,"given":"Juliette","family":"Charles","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6455-0831","authenticated-orcid":true,"given":"Paul-Arthur","family":"Meslin","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1626-0627","authenticated-orcid":true,"given":"H\u00e9l\u00e8ne","family":"Pasquer","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cit\u00e9, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9987-7237","authenticated-orcid":true,"given":"Rathana","family":"Kim","sequence":"additional","affiliation":[{"name":"Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint 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