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

Camille Vaganay1, Frank Ling1, Lois M Kelly1

  • 1Inserm U1342, IRSL, Paris Saint-Louis Leukemia Institute, Saint Louis Hospital, University of Paris-Cité, 75010 Paris, France.

Science Translational Medicine
|July 8, 2026
PubMed

Insights

Splicing dysregulation drives chemotherapy resistance in acute myeloid leukemia (AML). Targeting the SRRM1-CLK/PAK network and MAP2K5 splicing offers a novel strategy to overcome AML relapse and enhance treatment efficacy.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Chemotherapy resistance is a significant obstacle in treating acute myeloid leukemia (AML).
  • Splicing dysregulation has emerged as a key factor contributing to chemoresistance in AML.
  • Identifying specific molecular targets is crucial for developing effective AML therapies.

Purpose of the Study:

  • To investigate the role of splicing dysregulation in AML chemotherapy resistance.
  • To uncover molecular networks and vulnerabilities in chemoresistant AML cells.
  • To explore therapeutic strategies targeting splicing pathways to overcome AML relapse.

Main Methods:

  • Multiomic profiling and in vivo functional genomics were employed.
  • Analysis of the SRRM1 splicing regulator and CLK1/4 and PAK1 kinase families.
  • Assessment of a specific PAK1 variant and MAP2K5 splicing in chemoresistance.
  • Inhibition of PAK1 and CLK1/4 in AML cell lines, primary cells, and mouse models.

Main Results:

  • Splicing dysregulation, involving SRRM1 and hyperactivated CLK1/4 and PAK1 kinases, was identified as a determinant of chemoresistance.
  • A relapse-associated PAK1 variant conferring chemotherapy resistance was discovered.
  • Combined inhibition of PAK1 and CLK1/4 mimicked SRRM1 loss effects, targeting chemoresistant AML.
  • MAP2K5 missplicing was identified as a critical downstream event sensitized cells to chemotherapy.

Conclusions:

  • The SRRM1-CLK/PAK kinase network represents a vulnerability in chemoresistant AML.
  • Targeting splicing dysregulation, including MAP2K5, offers a promising therapeutic strategy for AML.
  • This approach has the potential to overcome chemotherapy resistance and improve outcomes in AML patients.

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