Molecular Basis of Action of the Putative Oncogene BCL-6

假定癌基因 BCL-6 作用的分子基础

• 批准号: 8034680
• 负责人: VIVIAN J BARDWELL
• 金额: $ 30.17万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034680
• 关键词: Affect; B-Cell Lymphomas; B-Lymphocytes; BCL1 Oncogene; BCL6 gene; BMI1 gene; Biological Process; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Maintenance; Cells; Centroblast; Clinical Trials; Complex; Data; Development; Epigenetic Process; Eye; Fingers; Funding; Future; Gene Targeting; Grant; Growth; Hematopoiesis; Histones; Homologous Gene; Human; Human Development; In Vitro; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Mature B-Lymphocyte; Mediating; Molecular; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncogene Proteins; Oncogenes; Oncogenic; Phenotype; Play; Polycomb; Proteins; Proto-Oncogenes; Public Health; Regulation; Repression; Role; Site; Stem cells; Syndrome; Testing; Transcription Repressor/Corepressor; Ubiquitin; Work; Zinc Fingers; base; cardiogenesis; chromatin modification; craniofacial; design; embryonic stem cell; improved; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; mRNA Expression; male; mouse model; novel; public health relevance; reconstitution; therapeutic target; ubiquitin ligase; ubiquitin-protein ligase

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.

描述（由申请人提供）：原癌基因 BCL6 编码对正常淋巴细胞发育至关重要的 POZ/BTB-锌指转录抑制因子。当 BCL6 异常表达时，会导致弥漫性大 B 细胞淋巴瘤 (DLBCL) 的发展。在上一次资助期间，我们发现了一种新型辅阻遏物 BCOR，它与 BCL6 一起发挥作用。在本次资助期间，我们已经证明 BCOR 与多种多梳族 (PcG) 蛋白形成复合物，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对染色质进行表观遗传修饰的蛋白。我们发现 BCOR 存在于多个 BCL6 靶基因上，这些基因的抑制可能导致淋巴瘤发生。因此，BCOR复合物的蛋白质为B细胞淋巴瘤的治疗提供了候选治疗靶点。我们还发现 BCOR 是逆转录病毒诱导的 B 细胞淋巴瘤中的常见插入位点，并且这些整合导致 BCOR mRNA 表达升高。这强烈表明 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 的突变会导致雄性致命的 X 连锁眼面心齿 (OFCD) 综合征，并且我们发现 Bcor 的亚等位性小鼠突变部分模仿了 OFCD 表型。最后，不适当的 BCOR 和 NSPC1 水平会破坏 ES 细胞分化，这与 BCOR 复合物在干细胞维持或分化中的作用一致。我的中心假设是，BCOR 通过表观遗传机制介导的抑制对于淋巴瘤的发生很重要。该提案的目的是：首先，确定 BCOR 在细胞培养和体内 B 细胞淋巴瘤发生中的作用；其次，剖析 BCOR 抑制复合物的分子和表观遗传机制。这里提出的工作在几个方面都很重要。首先，BCL6 参与临床上重要的 B 细胞淋巴瘤，而 BCOR 复合物是介导 BCL6 致癌活性的有力候选者。其次，我们的初步数据表明 BCOR 也可以充当癌基因。第三，这些研究将有助于阐明 BCOR 表观遗传抑制机制，该机制与许多生物过程相关，包括眼睛、颅面和心脏发育以及造血和淋巴瘤发生。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具有明确的相关性。 BCL6 是一种重要的癌蛋白，涉及高达 50% 的 DLBCL（非霍奇金淋巴瘤的常见亚型），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 也充当癌蛋白。部分基于这笔拨款资助的工作的潜在疗法已经接近临床试验，这里提出的工作应该允许设计未来改进的抗淋巴瘤疗法。