Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes

Elena Tonc, Yoshiko Takeuchi, Chun Chou, Yu Xia, Melanie Holmgren, Chika Fujii, Saravanan Raju, Gue Su Chang, Masahiro Iwamoto, Takeshi Egawa

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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 facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages 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 of patients with MYC-high B-cell acute lymphoblastic leukemia. 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. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.

Original languageEnglish
Pages (from-to)2526-2538
Number of pages13
Issue number24
StatePublished - Dec 16 2021


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