1. RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition
- Author
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Fan, Amy C., Nakauchi, Yusuke, Bai, Lawrence, Nuno, Armon Aziz Kevin A., Kohnke, 3.Feifei Zhao Thomas, Karigane, Daiki, Cruz-Hernandez, David, Reinisch, Andreas, Khatri, Purvesh, and Majet, Ravindra
- Subjects
Oncology, Experimental ,Gene mutations -- Research ,Interleukin-3 -- Health aspects ,Leukemia -- Development and progression -- Genetic aspects -- Drug therapy ,Stem cells -- Health aspects ,Cellular signal transduction -- Research ,Cancer -- Research ,Transcription factors -- Health aspects ,Health care industry - 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 RUNXI-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 RUNXI-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents., Introduction While aberrant immune signaling is a hallmark of many cancers, the mechanisms underlying dysregulated inflammatory signaling and the environmental cues driving disease pathogenesis are still being unraveled. In the [...]
- Published
- 2023
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