文章：

ABL1激酶在AML1-ETO和NUP98-PMX1白血病中作为肿瘤抑制因子

ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias

原文发布日期：2023-03-23

DOI: 10.1038/s41408-023-00810-0

类型: Article

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英文摘要：

Deletion of ABL1 was detected in a cohort of hematologic malignancies carrying AML1-ETO and NUP98 fusion proteins. Abl1−/− murine hematopoietic cells transduced with AML1-ETO and NUP98-PMX1 gained proliferation advantage when compared to Abl1 + /+ counterparts. Conversely, overexpression and pharmacological stimulation of ABL1 kinase resulted in reduced proliferation. To pinpoint mechanisms facilitating the transformation of ABL1-deficient cells, Abl1 was knocked down in 32Dcl3-Abl1ko cells by CRISPR/Cas9 followed by the challenge of growth factor withdrawal. 32Dcl3-Abl1ko cells but not 32Dcl3-Abl1wt cells generated growth factor-independent clones. RNA-seq implicated PI3K signaling as one of the dominant mechanisms contributing to growth factor independence in 32Dcl3-Abl1ko cells. PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1−/− cells when compared to the Abl1 + /+ counterparts. Since the role of ABL1 in DNA damage response (DDR) is well established, we also tested the inhibitors of ATM (ATMi), ATR (ATRi) and DNA-PKcs (DNA-PKi). AML1-ETO;Abl1−/− and NUP98-PMX1;Abl1−/− cells were hypersensitive to DNA-PKi and ATRi, respectively, when compared to Abl1 + /+ counterparts. Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors.
 

摘要翻译： 

在一组携带AML1-ETO和NUP98融合蛋白的血液系统恶性肿瘤中检测到ABL1缺失。与Abl1+/+细胞相比，转导了AML1-ETO和NUP98-PMX1的Abl1−/−鼠类造血细胞获得了增殖优势。相反，ABL1激酶的过表达及药物刺激则导致增殖减少。为明确ABL1缺陷细胞促进转化的机制，我们通过CRISPR/Cas9技术在32Dcl3-Abl1ko细胞中敲低Abl1，随后进行生长因子撤除挑战。32Dcl3-Abl1ko细胞（而非32Dcl3-Abl1wt细胞）产生了生长因子非依赖性克隆。RNA测序提示PI3K信号通路是导致32Dcl3-Abl1ko细胞获得生长因子非依赖性的主要机制之一。与Abl1+/+细胞相比，PI3K抑制剂布帕利西布对Lin-cKit+ NUP98-PMX1;Abl1−/−细胞具有选择性活性。鉴于ABL1在DNA损伤应答中的作用已明确，我们还测试了ATM抑制剂、ATR抑制剂和DNA-PKcs抑制剂。相较于Abl1+/+细胞，AML1-ETO;Abl1−/−和NUP98-PMX1;Abl1−/−细胞分别对DNA-PK抑制剂和ATR抑制剂表现出超敏性。此外，ABL1激酶抑制剂增强了细胞对PI3K、DNA-PKcs和ATR抑制剂的敏感性。综上所述，我们的研究表明ABL1激酶在AML1-ETO和NUP98-PMX1诱导的血液系统恶性肿瘤中发挥抑癌作用，并调节细胞对PI3K和/或DNA损伤应答抑制剂的反应。

原文链接：

ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias