Conditional C-Myc Inactivation Impacts on Chromosomal Translocation Mechanisms and B Lymphomagenesis

Abstract 5238

The requirement for Myc oncogenes in cellular transformation and tumor progression in human cancers has been studied extensively. Others and we have shown that the spontaneous development and progression of B lymphomas involving translocations that activate c-Myc can be faithfully recapitulated in model systems. However, for other oncogenes that are the predominant translocation targets in hematopoietic malignancies in humans, such as Bcl6, animal models that spontaneously promote translocations involving them are still lacking. Importantly, the molecular basis for the recurrence of particular oncogene translocations remains undefined. We have shown that a breakdown in DNA double strand break (DSB) repair resulting from conditionally inactivating the essential non-homologous end-joining (NHEJ) repair gene XRCC4 in p53 (XcP) deficient mature B cells reproducibly leads to the development of mature B lymphomas. These lymphomas, termed CD21/XcP, routinely harbor a clonal translocation that fuses IgH switch (S) regions to exon 1 of c-Myc, which we showed are formed by the aberrant repair of AID-induced DSBs during IgH Class Switch Recombination (CSR). These lymphomas harbor also a second clonal translocation that fuses the Igl locus into various chromosomal locations, including c-Myc, which our studies showed were formed by aberrant V(D)J recombination. Juxtaposition of Ig heavy chain (IgH) sequences to the c-Myc oncogene is one of the most extensively modeled and well-studied translocations. It is a hallmark of Burkitts Lymphoma, a subset of other B lymphomas. By limiting or eliminating c-Myc via conditional c-Myc inactivation in peripheral naïve and GC B cells in wildtype, p53 deficient and combined XRCC4 and p53 deficient settings, our studies reveal new insights into normal, functional requirements for C-myc in peripheral B lymphocytes, selection mechanisms underlying its activation in B lymphomagenesis, and the identification of new oncogenic translocation partners resulting from its inactivation in the CD21/XcP model.