转录因子RUNX1中的疾病启动突变以遗传和体细胞事件的形式发生，导致患者预后特别差的白血病。然而，RUNX1在白血病发生中的作用尚未完全理解，并且针对RUNX1突变白血病的有效治疗仍然难以找到。在这里，我们使用原发性患者样本和RUNX1敲除模型中的原代人类造血细胞研究了RUNX1丧失如何促进白血病进展，并确定了可靶向的脆弱点。令人惊讶的是，我们发现RUNX1丧失会降低增殖能力和干细胞功能。然而，RUNX1缺乏的细胞选择性上调了白介素-3（IL-3）受体。与IL-3接触，而不是其他JAK/STAT细胞因子，可以解救RUNX1 KO的增殖和竞争缺陷。此外，我们证明了RUNX1丧失抑制了JAK/STAT信号传导，并使RUNX1缺乏的细胞对JAK抑制剂敏感。我们的研究发现了RUNX1突变白血病对IL-3/JAK/STAT信号传导的依赖性，这可能使这些侵袭性血液癌症能够通过现有药物进行靶向治疗。

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.