Abstract TRAF3 is a novel tumor suppressor identified in human non-Hodgkin lymphoma and multiple myeloma. We recently reported that TRAF3 deletion causes vastly prolonged survival of mature B cells, which eventually leads to B lymphoma development in mice. The long latency of B lymphoma development observed in B-TRAF3−/− mice suggest that additional oncogenic pathways are required for B lymphomagenesis. To delineate such oncogenic pathways in TRAF3−/− B lymphomas, we performed microarray analyses and identified Sox5 as a gene recurrently up-regulated in B lymphomas spontaneously developed in different individual B-TRAF3−/− mice. We confirmed the striking up-regulation of Sox5 expression in TRAF3−/− B lymphomas at both the mRNA and protein levels by quantitative real time PCR and Western blot analyses, respectively. We further cloned the full-length cDNA of Sox5 from B lymphomas derived from 4 different individual B-TRAF3−/− mice. Surprisingly, we found that the sequence of Sox5 expressed in TRAF3−/− B lymphomas represents a novel isoform of Sox5, which has not been previously reported. This new isoform of Sox5 contains a 35 aa deletion in the N-terminal region in front of the leucine zipper domain. When transduced into human multiple myeloma cells, the cloned Sox5 cDNA was expressed into a protein of 80 kDa, a size identical to that detected in TRAF3−/− B lymphomas. Taken together, our findings identified a novel isoform of Sox5 as a candidate oncogene in B lymphoma. Our ongoing experiments will further elucidate the roles and mechanisms of Sox5 in TRAF3 deficiency-initiated B cell malignant transformation. This study is supported by a seed grant from the New Jersey Commission on Cancer Research (10-1066-CCR-EO, P. Xie), a Faculty Research Grant (P. Xie), and the Arthur Herrmann Endowed Cancer Research Fund (P. Xie); supported in part by a grant from NCI (R. Hart) and an Aresty Research Grant (A. Desai). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-272. doi:1538-7445.AM2012-LB-272