Molecular mechanisms of TRAF3-deficient B lymphomagenesis

B cell neoplasms, including leukemias, lymphomas and myelomas, are a common type of cancer, but they remain difficult to treat. This outlines a need for a better understanding of the mechanisms by which malignant transformation occurs, in order to come up with better therapeutic strategies. Recently, TRAF3 has been shown to act as a tumor suppressor, as mice with this gene specifically deleted in B cells develop B lymphomas. TRAF3 deletion causes prolonged B cell survival, allowing other secondary oncogenic alterations to occur. To elucidate these secondary alterations, we performed microarray analyses to identify genes which are differentially expressed in mouse B lymphomas. Two such genes that I have investigated in my thesis research are MCC and Sox5, both of which are significantly upregulated specifically in malignant B cells. MCC, mutated in colorectal cancer, has been previously identified as a tumor suppressor in colorectal cancer. We discovered that in malignant B cells, MCC acts as an oncogene to promote B cell survival and proliferation by modulating the signaling network centered at PARP1 and PHB1/2. The Sox5 gene encodes a transcription factor. Interestingly, we found that the Sox5 expressed in TRAF3 /- mouse B lymphomas represents a novel isoform of Sox 5, Sox5-BLM, which regulates malignant B cell proliferation by affecting the expression of p27 and B-catenin. These two genes have the potential to be used as diagnostic markers and therapeutic targets in B cell malignancies. Based on the understanding of TRAF3 signaling mechanisms, we also conducted translational studies using anti-cancer drugs to manipulate TRAF3 downstream signaling components. We have tested drugs targeting NF-kB2 and PKCd, and found that oridonin and AD198 exhibit potent anti-tumor activities on B cell neoplasms with TRAF3 deletions or mutations. Furthermore, oridonin or AD 198 drastically potentiated the anti-cancer effects of bortezomib, an effective clinical drug for multiple myeloma. Taken together, our studies have gained new insights into the mechanisms underlying TRAF3 inactivation-initiated B lymphomagenesis, and have discovered novel therapeutic targets for B cell neoplasms. Our findings also provide a rationale for clinical evaluation of several drugs or drug combinations in the treatment of B cell malignancies.Ph.D.Includes bibliographical referencesby Shanique Katrice Elaine Edward