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.

中文翻译：

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MYC-FBW7 磷酸化子的种系点突变引发造血系统恶性肿瘤

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 磷酸化蛋白中发生点突变，包括苏氨酸 58 (T58)，其中磷酸化允许通过 FBW7 泛素连接酶结合，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 (T58A) 处的丙氨酸突变引入小鼠种系的内源性c-Myc位点。虽然 MYC-T58A 小鼠发育正常，但大约 60% 的成年纯合 T58A 小鼠出现淋巴瘤和骨髓性白血病。我们发现，来自 MYC-T58A 小鼠的原始造血祖细胞表现出通常与造血干细胞 (HSC) 相关的异常自我更新，并上调对维持干细胞/祖细胞平衡很重要的 MYC 靶基因子集。在淋巴细胞中，与 WT MYC 相比，所有启动子处 MYC-T58A 的基因组占有率均增加，而以 T58A 依赖性方式差异表达的基因明显更接近 MYC 结合的增强子。 MYC-T58A 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激活。我们的数据表明，稳定 MYC 的单点突变足以扭曲靶基因表达，从而在与自我更新和淋巴瘤和白血病起始相关的多能造血祖细胞中产生显着的功能增益。