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细胞的新型干细胞白血病/淋巴瘤 在过去的三年中，已经描述了髓样谱系。 最多 患者患有周围淋巴结肿大和淋巴结活检的患者 通常显示T细胞淋巴细胞淋巴瘤。 伴有骨髓 另一方面，活检通常证明了髓样增生 明显的嗜酸性粒细胞。 淋巴瘤对治疗的反应很好，但大多数 患者发展为成熟的，迅速致命的急性骨髓 白血病。 值得注意的是，该综合征患者已经平衡 相互易位，涉及染色体带8p11和13q11-12， 在淋巴瘤外周节和骨髓增生性中都 骨髓细胞。 该观察结果表明易位（8; 13）是 在多功能细胞中的关键致癌事件， 髓样和淋巴样分化。 我们已经映射了易位 （8; 13）使用分子细胞遗传学方法的断点，并具有 将8p断点局部定位到70 kb细菌人造染色体 （BAC）克隆。 我们的初步BAC cDNA筛选研究已与 FGFRI是易位（; 13）中的一个候选基因。 我们假设 易位8p断点处的基因是致癌的，是 通过与13号染色体上的癌基因并置与癌基因并置。 我们将通过评估FGFRI的t（813）淋巴瘤来回答这些假设 基因组重排和异常转录本。 如果这些研究是 负面，我们将继续筛选出所选cDNA库的表达 序列映射到8p易位断点区域。 候选人 致癌基因将通过序列分析确定，并将用作 t（8; 13）淋巴瘤细胞cDNA的南部和北印迹中的探针 检测南部和/或北印迹的重新排列碎片将是 用作鉴定染色体13上相应的癌基的锚点， 对于两个基因，将分离出全长cDNA。 生物学作用 将评估T（8; 13）癌蛋白 - 均在生理学中 造血和白血病发生 - 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