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

Disease-initiating mutations in the transcription factor RUNXl 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 forRL/A/X7-mutant leukemias remain elusive. Here, w...

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Bibliographic Details
Published in:The Journal of clinical investigation 2023-10, Vol.133 (19), p.1-14
Main Authors: Fan, Amy C, Nakauchi, Yusuke, Bai, Lawrence, Azizi, Armón, Nuno, Kevin A, Zhao, Feifei, Köhnke, Thomas, Karigane, Daiki, Cruz-Hernandez, David, Reinisch, Andreas, Khatri, Purvesh, Majeti, Ravindra
Format: Article
Language:English
Subjects:
Biomedical research
Blood
Cancer
Cell death
Cloning
CRISPR
Cytokines
Disease
Genes
Hematological diseases
Hematopoietic stem cells
Interleukin 3
Kinases
Leukemia
Leukemogenesis
Medical prognosis
Mutants
Mutation
Patients
Proteins
Runx1 protein
Stem cells
Thrombocytopenia
Transcription factors
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Summary:Disease-initiating mutations in the transcription factor RUNXl 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 forRL/A/X7-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-K0 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-K0 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 RU/VXT-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI167053.