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December 8, 2025Blood

Clonal evolution and therapeutic vulnerabilities in SETBP1-mutated leukemia: Insights from physiological mouse model and integrative functional screens

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Authors

KNKoutarou NishimuraATAtsushi TanakaMMMasashi Matsuda

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Overview

Research uncovers clonal evolution and monocytosis in chronic myelomonocytic leukemia, indicating targeted therapies may improve outcomes.

Key Points

  • This research aims to elucidate the roles of SETBP1 and ASXL1 mutations in myeloid malignancies and identify therapeutic vulnerabilities.
  • Developed a blood-specific Setbp1 mutant locus knock-in mouse model
  • Conducted therapeutic screens using whole-genome CRISPR/sgRNA and drug libraries
  • Performed genetic and pharmacological validation of XPO1 dependency
  • Identified clonal evolution and monocytosis in Setbp1/Asxl1 double knock-in mice
  • XPO1 inhibition demonstrated a 20.8-fold reduction in cell growth during CRISPR screens
  • Selinexor monotherapy extended survival beyond 110 days in SETBP1-mutated AML models

Cite This Study

Nishimura et al. (2025) studied this question.

synapsesocial.com/papers/69362f764fa91c937236e37bhttps://doi.org/10.1182/blood-2025-989
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