Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan.
Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Leukemia. 2023 Sep;37(9):1802-1811. doi: 10.1038/s41375-023-01970-5. Epub 2023 Jul 18.
SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.
SETBP1 是一种潜在的表观遗传调节因子，其热点突变阻止了蛋白酶体降解，在预后不良的髓系恶性肿瘤中经常被检测到。人们认为，突变的 SETBP1 发挥了野生型 SETBP1 的放大效应，而不是新功能。这表明 SETBP1 的定量调控失调会导致造血细胞的转化。然而，关于内源性 SETBP1 在恶性和正常造血中的作用知之甚少。因此，我们整合了对原发性 AML 和健康样本、癌细胞系以及新生成的 Vav1-iCre;Setbp1 小鼠模型的分析。尽管 SETBP1 在长期造血干细胞中表达，但在正常造血中耗尽 SETBP1 很少改变体内自我更新、分化或重建。事实上，它的缺失并没有深刻地改变转录或染色质可及性。此外，尽管高 SETBP1 mRNA 的 AML 与不良预后的遗传和临床特征相关，但 SETBP1 对于 AML 的发展或维持并非必需。与 SETBP1 突变仅限于髓系恶性肿瘤的证据相反，在 AML 中没有观察到对 SETBP1 mRNA 表达的依赖性。这些出乎意料的结果揭示了一个未被认识的观点，即当蛋白质降解机制受损时，生理上非必需的基因可以作为癌基因发挥作用。
