A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies.
A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies.
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MYC-FBW7 磷酸化蛋白中的种系点突变引发造血系统恶性肿瘤。
DOI：
10.1101/2023.10.23.563660
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Eisenman,RobertN
中科院分区：
文献类型：
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作者：
Freie,Brian;Carroll,PatrickA;Varnum-Finney,BarbaraJ;Ramani,Vijay;Bernstein,Irwin;Eisenman,RobertN
癌症中MYC的致癌激活主要涉及转录增加而不是编码区突变。然而，MYC依赖性淋巴瘤经常在MYC磷酸降解决定子中获得点突变，包括在苏氨酸58（T58）处，其中磷酸化允许通过FBW 7泛素连接酶结合，从而触发MYC降解。为了了解T58磷酸化在正常细胞生理学中的功能，我们将T58（T58 A）处的丙氨酸突变引入小鼠生殖系中的内源性c-Myc基因座。虽然MYC-T58 A小鼠发育正常，但在大约60%的成年纯合子T58 A小鼠中出现淋巴瘤和骨髓性白血病。我们发现，MYC-T58 A小鼠的原始造血祖细胞表现出异常的自我更新，通常与造血干细胞（HSC）和上调MYC靶基因的一个子集，在维持干/祖细胞平衡的重要。在淋巴细胞中，与WT MYC相比，MYC-T58 A在所有启动子处的基因组占用率均增加，而以T58 A依赖性方式差异表达的基因显著更接近MYC结合的增强子。MYC-T58 A淋巴细胞祖细胞表现出代谢改变，并减少炎症和凋亡途径的活化。我们的数据表明，一个稳定MYC的单点突变足以使靶基因表达偏斜，在与自我更新和淋巴瘤和白血病的发生相关的多潜能造血祖细胞中产生功能的深刻增益。
Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in∼ 60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and up-regulate a subset of MYC target genes important in maintaining stem/progenitor cell balance. In lymphocytes, genomic occupancy by MYC-T58A was increased at all promoters compared with WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation stabilizing MYC is sufficient to skew target gene expression, producing a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.