Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia.
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Cancer Res. 2017 Dec 15;77(24):6818-6824. doi: 10.1158/0008-5472.CAN-17-0319. Epub 2017 Oct 20.
Mutations in the gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated posttranscriptionally by cytotoxic agents in C57BL/6 mice and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any antiproliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacologic modulation of RUNX1 might be an attractive new approach to treat hematologic malignancies. .
基因中的突变与急性髓系白血病 (AML)、T 细胞急性淋巴细胞白血病和骨髓增生异常综合征患者的化疗耐药和预后不良有关。然而，将 RUNX1 与治疗成功联系起来的潜在机制仍不清楚。在这里，我们探讨了这样一种假设，即 RUNX1 直接参与造血细胞对细胞毒性药物的反应。细胞毒性药物在 C57BL/6 小鼠和造血细胞系中会在后转录水平上调 RUNX1。在用阿糖胞苷治疗后，也可以在原发性人类 AML 细胞中看到上调。过表达时，RUNX1 限制增殖、促进凋亡并增强 DNA 损伤反应。RUNX1 的这种未知活性需要完整的 runt 同源结构域 (RHD)，大多数白血病相关点突变簇都在这个结构域中。与此一致的是，两种 RHD 缺陷型 RUNX1 蛋白缺乏任何增殖或凋亡活性，并且在某些条件下，在 Ba/F3 细胞中过表达时，RHD 缺陷型 (K83N、N109D) 突变 RUNX1 赋予对电离辐射的抗性。我们的实验揭示了 RUNX1 的一个新功能，并为基因突变与化疗和放疗耐药之间的联系提供了一个解释。此外，这些数据表明，药物调节 RUNX1 可能是治疗血液恶性肿瘤的一种有吸引力的新方法。
