Molecular Basis of Action of the Putative Oncogene BCL-6

描述(申请人提供)：原癌基因BCL6编码一个POZ/BTB-锌指转录抑制物，对正常的淋巴细胞发育是必不可少的。当bcl6基因异常表达时，会导致弥漫性大B细胞淋巴瘤(DLBCL)的发生。在上一次授予期间，我们发现了一种新的辅阻遏子BCOR，它与BCL6一起发挥作用。在这一资助期间，我们已经证明BCOR与几个多梳基(PcG)蛋白形成复合体，包括NSPC1(BMI1同源物)、泛素-H2A E3连接酶、RNF2和其他可能能够进一步表观修饰染色质的蛋白质。我们发现BCOR存在于多个BCL6靶基因上，这些基因的抑制可能有助于淋巴肿大的发生。因此，BCOR复合体的蛋白质为B细胞淋巴瘤的治疗提供了候选的治疗靶点。我们还发现，在逆转录病毒诱导的B细胞淋巴瘤中，BCOR是一个常见的插入位点，这些整合导致BCOR mRNA表达增加。这有力地表明，BCOR是一种癌基因。BCOR在人类发展中也发挥着更广泛的作用。人类BCOR的突变会导致男性致死性X连锁眼面部心脏综合征(OFCD)，我们发现BCOR的一个低态突变部分模仿了OFCD的表型。最后，不适当的BCOR和NSPC1水平会扰乱ES细胞的分化，这与BCOR复合体在干细胞维持或分化中的作用是一致的。我的中心假设是，通过表观遗传机制，BCOR介导的抑制对淋巴肿大是重要的。这项建议的目的是：第一，确定BCOR在细胞培养和体内B细胞淋巴瘤发生中的作用；第二，剖析BCOR抑制复合体的分子和表观遗传学机制。这里提出的工作在几个方面具有重要意义。首先，BCL6与临床上重要的B细胞淋巴瘤有关，BCOR复合体是介导BCL6致癌活性的有力候选者。其次，我们的初步数据表明，BCOR也可以作为癌基因发挥作用。第三，这些研究将有助于阐明BCOR表观遗传抑制机制，这些机制与许多生物学过程有关，包括眼睛、颅面和心脏发育以及造血和淋巴肿大。第四，我们的研究将有助于确定DLBCL的潜在治疗靶点。公共卫生相关性：这项工作与公共卫生有明显的相关性。Bcl6是一种重要的癌蛋白，参与了高达50%的DLBCL，DLBCL是一种常见的非霍奇金淋巴瘤亚型，我们的数据表明BCOR与BCL6一起发挥作用。我们的初步数据表明，BCOR也是一种癌蛋白。一种潜在的疗法已经接近临床试验，这项工作部分是基于这笔赠款资助的工作，这里提出的工作应该可以设计出未来改进的抗淋巴瘤疗法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.