A MYC-inducible tumor-suppressor program protects developing B cells from transformation

Abstract

Abstract Rapid expansion of developing and activated lymphocytes is essential for establishment of a diverse antigen receptor repertoire and effective immune responses. c-MYC is a multifunctional transcription factor required for regulated proliferation of lymphocytes and their progenitors. However, c-MYC is also strongly oncogenic, both in humans and mice. Nonetheless, transformation of lymphocytes is rare, despite their extensive proliferative activity and endogenous DNA damage caused by RAG and AID activities. Thus, we hypothesized that lymphocytes are protected from transformation by unique tumor suppressor programs, potentially linked with c-MYC activity. Using the Eμ-Myc mouse model, we identified a c-MYC inducible tumor suppressive program mediated by its direct target, transcription factor AP4/Tfap4. AP4 haploinsufficiency significantly accelerated tumorigenesis of developing B cells in a cell-intrinsic manner. These tumors frequently underwent loss-of-heterozygosity of the remaining Tfap4 allele, a hallmark characteristic of other tumor suppressors. Functionally defective somatic variants of AP4 were also identified in primary human lymphomas. Mechanistically, AP4 suppressed expression of the oncogene Erg in developing B cells, which is normally suppressed in c-MYC+ pro/pre-B cells. Reducing Erg expression significantly prolonged the survival of AP4 heterozygous Eμ-Myc mice. AP4 thus protects developing B cells from transformation, at least in part, by restricting co-expression of MYC and additional oncogenes. Our findings indicate that c-MYC engages an active tumor suppressive program in B cells by inducing its direct target AP4, which is the first example of c-MYC-inducible tumor suppressors.