Splicing-associated network PAK1-CLK1/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia.

Authors

Camille Vaganay, Frank Ling, Lois M Kelly, Juliette Charles, Paul-Arthur Meslin, Hélène Pasquer, Rathana Kim, Marie Passet, Matthieu Duchmann, Léa Pelissier-Menjaud, Séverine Lecourt, Angela H Su, Emmanuelle Latour, Christopher F Bassil, Gabriela Alexe, Gael Fortin, Duong Ho Nhat, Cécile Culeux, Carine Legrand, Sofiane Fodil, Tony Huynh, Khansa Saadallah, Azucena Ramos, Bérangère Lombard, Damarys Loew, Christopher D Delaney, Catherine Lonchamp, Morgane Fontaine, Kim Pacchiardi, Anja Kocijancic, Lisa Aziez, Nina Fenouille, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Michael T Hemann, Emmanuelle Clappier, Lina Benajiba, Kimberly Stegmaier, Kris C Wood, Raphaël Itzykson, Antoine Forget, Camille Lobry, Alexandre Puissant

Published in

Science translational medicine. Volume 18. Issue 857. Pages eadx3847. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

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 PAK1 variant, c.1429G>T p.(Ala⁴⁷⁷→Ser), that confers chemotherapy resistance. Combined PAK1 and CLK1/4 inhibition recapitulated the splicing changes induced by SRRM1 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 MAP2K5 upon SRRM1 depletion sensitized cells to chemotherapy. Our findings highlight a therapeutic strategy to overcome AML relapse by targeting splicing dysregulation.

PMID:
42418558
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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