The transcription factor c-MYC in lymphocyte expansion and restriction of stemness

摘要 淋巴细胞能够在抗原受体刺激下强劲扩张，是 最快的细胞分裂是在出生后。它们的增殖能力对于建立广泛的抗原至关重要。 在发育过程中的受体谱系，也用于快速放大抗原特异性免疫 病原体入侵。此外，T细胞也可以在体外进行扩增，用于实验或过继细胞疗法 以及CAR-T细胞的产生，这些细胞已经被转化为抗癌疗法。虽然如此健壮 T细胞的扩增产生了许多效应细胞，它们是短暂的和不可持续的有效 控制感染和癌症。这项拟议的研究的目标是剖析健壮的 增殖与分子水平上的这种分化有关。我们将阐明基因调控 由转录因子c-myc启动的网络，它是致癌的，但也是快速增殖的关键 许多检查点的淋巴细胞，发育中的淋巴细胞和成熟的淋巴细胞，并定义关键的MYC 下游基因与分化过程特别相关。从这些研究中获得的见解和 选择性地抑制分化过程将揭示未被认可的肿瘤抑制计划和 促进具有记忆/干细胞样特性的抗原特异性淋巴细胞的扩增 预防感染和癌症。

Abstract Lymphocytes are capable of robust expansion upon antigen receptor stimulation and are one of the most rapidly dividing cells postnatally. Their proliferation capacity is critical for establishing broad antigen receptor repertoires during development and also for rapidly amplifying antigen-specific immunity upon pathogen invasion. In addition, T cells can also be expanded ex vivo for experiments or adoptive cell therapies and the generation of CAR-T cells, which have been translated into anti-cancer therapies. While such robust expansion of T cells generates many effector cells, they are short-lived and unsustainable for efficacious control of infection and cancers. The goal of the proposed study is to dissect the mechanisms by which robust proliferation is coupled to such differentiation at the molecular level. We will elucidate the gene regulatory network initiated by the transcription factor c-MYC, which is oncogenic but also critical for rapid proliferation of lymphocytes at many checkpoints, in developing lymphocytes and mature lymphocytes, and define key MYC downstream genes specifically associated with the differentiation processes. Insights from these studies and selective inhibition of the differentiation processes will disclose unappreciated tumor suppressor programs and facilitate expansion of antigen-specific lymphocytes with memory/stem-like properties for long-lasting protection against infection and cancers.