TRAFs are the point of emergence of TNF Receptor (TNFR)-family signal transduction. They integrate the signaling from many members of the TNFR family and regulate NF""""""""B and c-jun, the reprogramming of gene expression, and the control of cell death. Deregulation of these pathways is causative of several autoimmune and inflammatory diseases. There is growing evidence indicating that TRAF2 might have a role in controlling B cell homeostasis. B cells lacking of TRAF2 have survival advantages and accumulate in transgenic mice. Furthermore, we have recently described that transgenic mice over-expressing in B lymphocytes both Bcl-2 and a TRAF2 mutant lacking the N-terminal RING and zinc finger domains (TRAF2DN), which mimics TRAF1, develop small B cell lymphoma and leukemia that have remarkably similar characteristics to human chronic lymphocytic leukemia (CLL). These results have provided the fist direct evidence that deregulation of TRAF signal pathways might be implicated in tumorigenesis. TRAF1 might regulate TRAF2-mediated activities and subcellular localization. Interestingly, we and others have shown that TRAF1 is highly over-expressed in some human hematopoietic malignancies, such as non-Hodgkin lymphomas (NHL) and particularly in chronic lymphocytic leukemias (CLL). However it is not clear whether or not TRAF1 upregulation has a role in the development and/or progression of the disease. We speculate that TRAF1 overexpression is directly involved in the development or maintenance of B cell malignancies. We propose to generate transgenic mice specifically expressing TRAF1 in B cells. These mice will help to answer the question on whether TRAF1 sensitizes B cells to malignancy. Also, we will elucidate whether TRAF1 cooperate with Bcl-2 in developing CLL. Furthermore we will further our characterization of the CLL-like leukemia developed by the TRAF2DN/Bcl-2 mice, using among other techniques cDNA arrays to determine the specific patterns of expression in this tumor cells. Our goal is to validate these mice as a preclinical model for chemotherapeutical drug testing. Therefore, the Aims of this proposal are: 1. Generation of transgenic mice expressing TRAF1 in B lymphocytes. 2. To assess the role of TRAF1 in predisposing B cells to malignancy and 3. Characterization of the CLL-like lymphoproliferative disorder caused by overexpression of TRAF2DN and Bcl-2 in B cells. ? ? ? ?
| Perez-Chacon, Gema; Llobet, David; Pardo, Constanza et al. (2012) TNFR-associated factor 2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia/small lymphocytic lymphoma in mice. J Immunol 189:1053-61 |
| Zapata, Juan M; Llobet, David; Krajewska, Maryla et al. (2009) Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer. Blood 113:4595-603 |
