Clonal expansion of lymphocytes during the development and immune responses is a hallmark feature of adaptive immunity. The transcription factor c-MYC is essential to establish metabolically activate states in activated lymphocytes and allow them to proceed into rapid division cycles. The c-MYC driven clonal expansion is beneficial for host protection by quantitatively amplifying functional lymphocyte populations. B lymphocytes also qualitatively improve antibody responses through MYC-dependent proliferative bursts in the Germinal centers. While c-MYC is thus very important for protective immunity, its aberrant expression has also been associated with many cancers in humans and mice. Indeed, MYC-expressing proliferating B cells in GCs and their precursors in the bone marrow are the major sources of B cell malignancies in humans, which might be worsened by the concurrent presence of genomic insults secondary to activities of RAG proteins and AID that not only target antigen receptor loci but also a number of cryptic targets. Then, how GC B cells or B cell precursors minimize the risk of deleterious outcomes while facing the need for MYC-driven clonal expansion? We have recently found that proliferating lymphocytes temporally restrict c-MYC expression during their clonal expansion. In the GCs, B cells use c-MYC only for the initiation of proliferative program and utilize its downstream factor AP4 to continue their divisions. This c-MYC-AP4 transcription factor hand-off is required for the requisite GC responses for the development of protective antibodies against chronic viral infection. Since this cascade allows GC B cells to spatially and temporally segregate c-MYC expression in the light zone and AID activity in the dark zone, this mechanism may indirectly or passively contribute to protection of GC B cells if AP4 is less oncogenic compared to c-MYC. Unexpectedly, we have obtained preliminary results indicating that AP4 functions as a tumor suppressor MYC-driven B cell leukemia in a completely independent set of experiments. These results suggest that the MYC-AP4 axis is essential to support requisite B cell proliferation for protective immunity and simultaneously protect proliferating B cells from oncogenic transformation. This may highlight a novel, counterintuitive function of a MYC-induced gene regulatory pathway that functions as a tumor suppressor. In this grant, we will study the mechanisms of MYC-independent maintenance of AP4 by T cell help signals, which is necessary for durable proliferation of normal B cells and those of AP4-mediated tumor suppression.
B cell proliferation during the development and immune responses is required for protective antibody responses, while its aberrant regulation results in increased incidence of cell death or transformation. It is unknown how the immune system enhances B cell proliferation and tolerate DNA damage during VDJ recombination during the development and genome mutagenesis in the normal germinal center responses without causing cancerous transformation. In this proposed study, we will determine the role of a transcription factor cascade that co-engages genetic programs for extensive B cell proliferation and tumor suppression.
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