TFAP4 mutations are found in more than 10% of cases of Burkitt Lymphoma, a hallmark B cell malignancy driven by high MYC expression.
Mechanistically, the c-MYC-induced TFAP4 suppresses tumorigenesis of B cells by limiting self-renewal and promoting differentiation.
The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC not only facilitates B cell proliferation as a pro-tumorigenic driver but unexpectedly also co-engages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival in MYC-high B-ALL cases. In mice, insufficient TFAP4 expression accelerated c-MYC-driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. The pursuant transcription factor cascade thus functions as a tumor suppressor module that safeguards against the transformation of developing B cells.