Myc Promotes Tumorigenesis by Supressing Nfkb2.

Rel/NF-kappaB transcription factors are mediators of immune responses, cell survival, and transformation, and are frequently deregulated in cancer. The NF-kappaB2 subunit is associated with chromosomal translocations or deletions in lymphoid malignancies, and deletion of the COOH-terminal ankyrin domain of NF-kappaB2 results in increased lymphocyte proliferation. Here, we report that activation of the Myc oncogene leads to suppression of Nfkb2 expression in early passage mouse embryonic fibroblasts and primary bone marrow-derived B cells. Accordingly, transgenic expression of c-Myc in the Eμ-Myc model of human Burkitt lymphoma results in reduced nfkb2 transcript and NF-kappaB2 p100 and p52 protein levels in pre-cancerous B cells. Nfkb2 expression is further reduced in the majority of Eμ-Myc lymphomas and in human Burkitt lymphoma. Nfkb2 suppression by Myc occurs at least in part by transcriptional repression as shown by promoter studies. To evaluate the relevance of Myc-mediated suppression of Nfkb2 for tumorigenesis, consequences of complete Nfkb2 loss were evaluated in vivo. In pre-cancerous B cells of Myc-transgenic mice, loss of Nfkb2 affects Myc-induced apoptosis while B cell proliferation is unaffected. Deletion of Nfkb2 results in an acceleration of lymphoma development in Eμ-Myc transgenic mice. Therefore, Myc-induced Nfkb2 suppression promotes lymphomagenesis.