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

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.