RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [RNA-seq]
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 use primary patient samples and a RUNX1 knockout 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 interleukin-3 (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 these aggressive blood cancers to be targeted with existing agents. Overall design: Comparative gene expression analysis of cord blood derived CD34+ gene edited at the AAVS1 or RUNX1 locus. 4 biological replicates.