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首页> 外文期刊>The journal of clinical investigation >Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
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Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells

机译：转录因子RUNX1促进急性髓细胞性白血病细胞的存活

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RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
机译：RUNX1通常被认为是骨髓肿瘤中的肿瘤抑制因子。在患有骨髓增生异常综合症（MDS）和细胞遗传学正常的急性髓性白血病（AML）的患者中经常发现失活的RUNX1突变。但是，在具有白血病生成融合蛋白的AML（如核心结合因子（CBF）白血病和MLL融合白血病）中未发现体细胞RUNX1改变，这增加了RUNX1可能真正促进这些白血病细胞生长的可能性。使用正常的人脐带血细胞和表达白血病生成融合蛋白的细胞，我们发现RUNX1在髓样白血病生成中具有双重作用。 RUNX1过表达通过诱导髓样细胞分化来抑制正常脐血细胞的生长，而AML1-ETO和MLL-AF9细胞的生长则需要一定水平的RUNX1活性。使用小鼠遗传模型，我们还显示Runx1 / Cbfb的联合丢失抑制了MLL-AF9诱导的白血病发展。 RUNX2可以弥补RUNX1的损失。 BCL2介导RUNX1在MLL融合性白血病中的生存作用。我们的研究揭示了RUNX1在髓样白血病发生中的意外生存作用。抑制RUNX1活性而不是增强它可能是具有致白血病融合蛋白的AML的有前途的治疗策略。

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