B-cell non-Hodgkin Lymphoma (B-NHL) represents the fifth most common cancer in humans. B-NHL is characterized by chromosomal translocations that juxtapose regulatory elements from the Immunoglobulin (Ig) loci to cellular proto-oncogenes causing their deregulated expression. These translocations often arise from mis-repair of programmed DNA double strand breaks (DSBs) generated during normal B cell development, specifically V(D)J recombination and Class Switch Recombination (CSR). Sequence analysis of normal Ig rearranged gene products as well as B-NHL-associated chromosomal translocations revealed extensive involvement of micro-homology (MH) at the junction, indicating an important role for MH-mediated end joining (MMEJ) in normal lymphocyte development as well as chromosomal translocations and lymphomagenesis. Yet the genetic components and the regulation ofthe MMEJ are largely unknown, as are their roles in lymphocyte development and lymphomagenesis. CtBP-interacting protein (CtlP, also called RBBP8) is essential for end-resection, necessary to expose homology sequences flanking the site of breaks for MMEJ. Here we propose to investigate the role of CtlP in oncogenic chromosomal translocations and lymphomagenesis arising from persistent DSBs during V(D)J recombination and CSR. In particular, in Aim 1 we will investigate whether CtlP is required for normal V(D)J recombination and V(D)J recombination- mediated chromosomal translocations and lymphomagenesis. In collaboration with other projects 1 (Symington), 2 (Gautier and Gottesman) and 4 (Baer), we will also determine if the function of CtlP in V(D)J recombination meditated translocations involves its interaction with BRCA1, CtBP and RB, as well as the regulation by PISK related protein kinase.
In Aim 2, we will investigate whether CtlP is required for CSR- mediated translocations and the development of B-NHL from mature gemrilnal center B cells. We will also determine if CtlP is required for MYC-induced lymphomagenesis and if CtlP is sufficient, when deregulated, to drive lymphomagenesis in transgenic mice. The latter experiments are based on our preliminary results, which identify CtlP as a potential transcriptional target of the c-MYC proto-oncogene in developing B cells.
B cell lymphomas often harbrar recurrent oncogenic chromosomal translocations. We propose to elucidate the roles of CtlP in generating oncogenic translocations that lead to B cell-malignancies and in Myc- mediated lymphomagenesis. Better understanding of fundamental processes that lead to B cell lymphoma, along with the novel mouse models we will generate, should facilitate devebpment of better treatments. Frequent interaction with investigators in this program will greatly enhance the accomplishment of our goals.
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