RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition
Amy C. Fan, … , Purvesh Khatri, Ravindra Majeti
Amy C. Fan, … , Purvesh Khatri, Ravindra Majeti
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(19):e167053. https://doi.org/10.1172/JCI167053.
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Research Article Hematology Inflammation

RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition

Abstract

Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood, and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-KO model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the IL-3 receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1-KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.

Authors

Amy C. Fan, Yusuke Nakauchi, Lawrence Bai, Armon Azizi, Kevin A. Nuno, Feifei Zhao, Thomas Köhnke, Daiki Karigane, David Cruz-Hernandez, Andreas Reinisch, Purvesh Khatri, Ravindra Majeti

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