激活集落刺激因子 3 受体基因 (CSF3R) 突变在伴有 t(8;21) 易位的急性髓系白血病 (AML) 中反复出现。然而，CSF3R 的改变和 t(8;21) 相关的 RUNX1-RUNX1T1 融合之间致癌协作的性质仍不清楚。在来自健康供体的 CD34 造血干细胞和祖细胞中，双癌基因表达导致克隆优势、自我更新潜力增加、原始细胞样形态和独特的免疫表型。基因表达谱揭示 Hedgehog 信号传导是一种潜在机制，而 GLI2 的上调构成了假定的药理学靶点。原代造血细胞和 t(8;21) 阳性 AML 细胞系 SKNO-1 在表达 CSF3R T618I 时均表现出对 GLI 抑制剂 GANT61 的敏感性增加。我们的研究结果表明，在白血病发生过程中，RUNX1-RUNXT1 融合和 CSF3R 突变以协同方式改变刺猬信号，可用于治疗。版权所有 © 2023 作者。由 Wolters Kluwer Health, Inc. 代表欧洲血液学协会出版。

Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.