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: 7612082
• 负责人: VIVIAN J BARDWELL
• 金额: $ 31.11万
• 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/7612082
• 关键词: Affect; B-Cell Lymphomas; B-Lymphocytes; 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; abstracting; 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; 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POZ/ btb -锌指转录抑制因子，对正常淋巴细胞发育至关重要。当BCL6异常表达时，可导致弥漫性大B细胞淋巴瘤（DLBCL）的发展。在上一个资助期间，我们发现了一种新的协同抑制因子BCOR，它与BCL6一起起作用。在这个资助期，我们已经证明BCOR与几种多梳群（PcG）蛋白形成复合物，包括NSPC1 （BMI1同源物）、泛素- h2a E3连接酶、RNF2和其他可能进一步修饰染色质的蛋白。我们发现BCOR存在于多个BCL6靶基因中，这些基因的抑制可能有助于淋巴瘤的发生。因此，BCOR复合物蛋白为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表达升高。这有力地表明BCOR是一种致癌基因。BCOR在人类发展中也发挥着更广泛的作用。人类BCOR突变导致雄性致死的X- linked oculofacocardiodental （OFCD）综合征，我们发现小鼠BCOR的一种半形突变部分模仿了OFCD表型。最后，不适当水平的BCOR和NSPC1可破坏胚胎干细胞分化，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介导的抑制，通过表观遗传机制，对淋巴瘤发生很重要。本研究的目的是：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，解剖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意义重大。首先，BCL6参与临床重要的B细胞淋巴瘤，BCOR复合物是介导BCL6致癌活性的强有力候选物。其次，我们的初步数据表明BCOR也可以作为致癌基因。第三，这些研究将有助于阐明BCOR的表观遗传抑制机制，该机制与许多生物学过程有关，包括眼睛、颅面、心脏发育以及造血和淋巴瘤形成。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显相关性。BCL6是一种重要的癌蛋白，与高达50%的DLBCL（非霍奇金淋巴瘤的一种常见亚型）有关，我们的数据表明BCL6在BCOR中起作用。我们的初步数据表明，BCOR也作为一种癌蛋白。已经有一种潜在的治疗方法，部分基于这项资助的工作，正在接近临床试验，这里提出的工作应该允许设计未来改进的抗淋巴瘤治疗方法。