TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA

干细胞白血病/淋巴瘤中 8-13 的易位

• 批准号: 2895778
• 负责人: JONATHAN Alfred FLETCHER
• 金额: $ 26.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-19 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895778
• 关键词: T lymphocyte; artificial chromosomes; bone marrow transplantation; cell transformation; chromosome translocation; clone cells; gene rearrangement; genetic library; hematopoiesis; hematopoietic stem cells; human tissue; laboratory mouse; leukemia; lymphocytic leukemia; lymphoma; molecular oncology; neoplasm /cancer genetics; neoplastic cell; neoplastic transformation; northern blottings; oncogenes; oncoproteins; plasmids; southern blotting; tissue donors

A novel variety of stem-cell leukemia/lymphoma involving T-cell, B-cell, and myeloid lineages has been described in the past three years. Most patients present with peripheral lymphadenopathy, and lymph node biopsies typically reveal T-cell lymphoblastic lymphoma. Concomitant bone marrow biopsy, on the other hand, generally demonstrates myeloid hyperplasia with pronounced eosinophilia. The lymphoma responds well to therapy, but most patients progress to a full-blown, rapidly fatal, acute myelogenous leukemia. It is notable that patients with this syndrome have balanced reciprocal translocation, involving chromosome bands 8p11 and 13q11-12, both in the lymphomatous peripheral nodes and in the myeloproliferative bone marrow cells. This observation suggests that translocation (8;13) is a critical oncogenetic event in a pluripotential cell capable of both myeloid and lymphoid differentiation. We have mapped the translocation (8;13) breakpoints using molecular cytogenetic approaches and have localized the 8p breakpoint to a 70 kb bacterial artificial chromosome (BAC) clone. Our preliminary BAC cDNA screening studies have implicated FGFRI as one candidate gene in the translocation (;13). We hypothesize that a gene at the translocation 8p breakpoint is oncogenic and is activated by juxtaposition with an oncogene on the chromosome 13 long arm. We will answer these hypotheses by evaluating t(813) lymphomas for FGFRI genomic rearrangements and aberrant transcripts. If those studies are negative, we will continue to screen selected cDNA libraries for expressed sequences mapping to the 8p translocation breakpoint region. Candidate oncogenes will be identified by sequence analysis and will be used as probes in Southern and Northern blots of t(8;13) lymphoma cells cDNAs detecting rearranged fragments on Southern and/or Northern blots will be used as anchors to identify the corresponding oncogene on chromosome 13, and full-length cDNAs will be isolated for both genes. Biologic role of the t(8;13) oncoproteins will be evaluated - both in physiologic hematopoiesis and in leukemogenesis - through in vitro and in vivo functional analysis.

涉及T细胞、B细胞 和骨髓谱系的研究。 最 患者存在外周淋巴结病，淋巴结活检 通常都是T细胞淋巴母细胞性淋巴瘤 伴随骨髓 另一方面，活检通常显示骨髓增生， 嗜酸性粒细胞增多 淋巴瘤对治疗反应良好，但大多数 患者进展为完全的、迅速致命的、急性髓细胞性 白血病 值得注意的是，患有这种综合征的患者 相互易位，涉及染色体带8 p11和13 q11 -12， 淋巴瘤性外周淋巴结和骨髓增生性 骨髓细胞 这一观察结果表明，易位（8;13）是 多能细胞中的关键致癌事件， 髓样和淋巴样分化。 我们已经绘制出了 （8;13）使用分子细胞遗传学方法的断点， 将8 p断裂点定位于70 kb细菌人工染色体 (BAC)分身 我们初步的BAC cDNA筛选研究表明， FGFRI作为易位中的一个候选基因（;13）。 我们假设 易位8 p断裂点处的基因是致癌的， 通过与13号染色体长臂上的癌基因并置而激活。 我们将回答这些假设通过评估t（813）淋巴瘤FGFRI 基因组重排和异常转录物。 如果这些研究 阴性，我们将继续筛选选择的cDNA文库， 定位到8 p易位断裂点区域的序列。 候选 将通过序列分析鉴定癌基因，并将其用作 t（8;13）淋巴瘤细胞cDNA的Southern和北方杂交探针 在Southern和/或北方印迹上检测重排的片段， 用作锚点以鉴定13号染色体上的相应致癌基因， 并分离两种基因的全长cDNA。 生物学作用 将评价t（8;13）癌蛋白--无论是在生理 造血和白血病-通过体外和体内 功能分析

项目成果

ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain.

• DOI: 10.1182/blood.v96.2.699.014k53_699_704
• 发表时间: 2000-07
• 期刊: Blood
• 影响因子: 20.3
• 作者: S. Xiao;Jennifer McCarthy;J. Aster;J. Fletcher

Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule.

• DOI: 10.1021/jm900424a
• 发表时间: 2009-06-25
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Gunaratnam M;Swank S;Haider SM;Galesa K;Reszka AP;Beltran M;Cuenca F;Fletcher JA;Neidle S
• 通讯作者: Neidle S