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YBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Leukemia ( IF 11.4 ) Pub Date : 2021-08-31 , DOI: 10.1038/s41375-021-01393-0
Florian Perner 1, 2, 3 , Tina M Schnoeder 3 , Yijun Xiong 1 , Ashok Kumar Jayavelu 4, 5, 6 , Nomusa Mashamba 7 , Nuria Tubio Santamaria 3 , Nicolas Huber 3 , Kristina Todorova 8 , Charles Hatton 1 , Birgit Perner 9, 10 , Theresa Eifert 3 , Ciara Murphy 1 , Maximilian Hartmann 2 , Jessica I Hoell 11 , Nicolas Schröder 12 , Sabine Brandt 13 , Andreas Hochhaus 2 , Peter R Mertens 13 , Matthias Mann 4 , Scott A Armstrong 1 , Anna Mandinova 8 , Florian H Heidel 2, 3, 14
Affiliation  

Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.



中文翻译:

YBX1 介导致癌转录物的翻译以控制 AML 中的细胞竞争

恶性克隆的持续存在是血液系统恶性肿瘤患者不良结局的主要决定因素。尽管大多数急性髓性白血病 (AML) 患者在化疗后达到完全缓解,但其中很大一部分由于残留的恶性细胞而复发。这些持久性克隆具有竞争优势,可以重新建立疾病。因此,明确需要专门减少恶性细胞的细胞竞争而使正常细胞不受影响的靶向策略。最近,我们小组将 YBX1 鉴定为JAK2突变的骨髓增生性肿瘤中疾病持续存在的介质。然而,到目前为止,YBX1 在 AML 中的作用仍然难以捉摸。在这里,YBX1的失活证实了其作为白血病发展和维持的重要驱动因素的作用。我们确定了它通过招募多体链来放大致癌转录物(包括 MYC)翻译的能力。YBX1的基因失活破坏了这一调节回路并取代了多核糖体的致癌驱动因素,随后蛋白质水平下降。结果,白血病细胞显示出增殖减少并且在体外和体内的竞争中胜出,而正常细胞基本上不受影响。总的来说,这些数据将 YBX1 确立为 AML 中的特定依赖性和治疗靶点,这对于致癌蛋白表达至关重要。

更新日期:2021-08-31
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