The proto-oncogene BCL6 encodes a POZ/BTB-zinc finger transcriptional repressor that is essential for normal lymphocyte development. When BCL6 is aberrantly expressed it leads to the development of diffuse large B cell lymphomas (DLBCL). During the last grant period we identified a novel corepressor, BCOR, which functions with BCL6. In this funding period we have shown that BCOR forms a complex with several polycomb group (PcG) proteins, including NSPC1 (a BMI1 homolog), the ubiquitin-H2A E3 ligase, RNF2, and other proteins potentially capable of further epigenetic modification of chromatin. We found that BCOR is present at multiple BCL6 target genes whose repression is likely to contribute to lymphomagenesis. Thus proteins of the BCOR complex provide candidate therapeutic targets for treatment of B cell lymphoma. We also have found that BCOR is a common insertion site in retrovirally-induced B cell lymphomas, and that these integrations cause elevated BCOR mRNA expression. This strongly suggests that BCOR acts as an oncogene. BCOR also plays a more widespread role in human development. Mutations in human BCOR cause the male-lethal X- linked Oculofaciocardiodental (OFCD) syndrome, and we showed that a hypomorphic mouse mutation in Bcor partially mimics the OFCD phenotype. Finally, inappropriate levels of BCOR and NSPC1 can disrupt ES cell differentiation, consistent with a role for the BCOR complex in stem cell maintenance or differentiation. My central hypothesis is that BCOR-mediated repression, via epigenetic mechanisms, is important for lymphomagenesis.
The aims of this proposal are: first, to determine the role of BCOR in B cell lymphomagenesis both in cell culture and in vivo and second, to dissect the molecular and epigenetic mechanisms of the BCOR repression complex. The work proposed here is significant in several respects. First, BCL6 is involved in clinically important B cell lymphomas and the BCOR complex is a strong candidate to mediate BCL6 oncogenic activity. Second, our preliminary data suggest BCOR also can act as an oncogene. Third, these studies will help elucidate BCOR epigenetic repression mechanisms, which are relevant to many biological processes including eye, craniofacial, and heart development as well as hematopoiesis and lymphomagenesis. Fourth, our studies will help identify potential therapeutic targets for DLBCL.
The work has clear relevance to public health. BCL6 is and important oncoprotein involved in up to 50% of DLBCL, a common subtype of non-Hodgkin's lymphoma, and our data indicate that BCOR functions with BCL6. Our preliminary data suggest that BCOR also acts as an oncoprotein. Already a potential therapy based in part on work funded by this grant is nearing clinical trials, and the work proposed here should permit the design of future improved anti-lymphoma therapy.
|Lefebure, Marcus; Tothill, Richard W; Kruse, Elizabeth et al. (2017) Genomic characterisation of E?-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene. Nat Commun 8:14581|
|Wong, Sarah J; Gearhart, Micah D; Taylor, Alexander B et al. (2016) KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1. Structure 24:1795-1801|
|Cao, Q; Gearhart, M D; Gery, S et al. (2016) BCOR regulates myeloid cell proliferation and differentiation. Leukemia 30:1155-65|
|Béguelin, Wendy; Teater, Matt; Gearhart, Micah D et al. (2016) EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell 30:197-213|
|Oliviero, Giorgio; Munawar, Nayla; Watson, Ariane et al. (2015) The variant Polycomb Repressor Complex 1 component PCGF1 interacts with a pluripotency sub-network that includes DPPA4, a regulator of embryogenesis. Sci Rep 5:18388|
|Yang, Jessica A; Tubo, Noah J; Gearhart, Micah D et al. (2015) Cutting edge: Bcl6-interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function. J Immunol 194:5604-8|
|Junco, Sarah E; Wang, Renjing; Gaipa, John C et al. (2013) Structure of the polycomb group protein PCGF1 in complex with BCOR reveals basis for binding selectivity of PCGF homologs. Structure 21:665-71|
|Hatzi, Katerina; Jiang, Yanwen; Huang, Chuanxin et al. (2013) A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep 4:578-88|
|Wamstad, Joseph Alan; Corcoran, Connie Marie; Keating, Anne Marjorie et al. (2008) Role of the transcriptional corepressor Bcor in embryonic stem cell differentiation and early embryonic development. PLoS One 3:e2814|
|Ghetu, Alexandru F; Corcoran, Connie M; Cerchietti, Leandro et al. (2008) Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell 29:384-91|
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