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: 2769908
• 负责人: JONATHAN Alfred FLETCHER
• 金额: $ 21.91万
• 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/2769908
• 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.

一种新型干细胞白血病/淋巴瘤，涉及 T 细胞、B 细胞、 过去三年中已经描述了骨髓谱系。 最多 患者出现外周淋巴结肿大和淋巴结活检 通常提示 T 细胞淋巴母细胞淋巴瘤。 伴随骨髓 另一方面，活检通常显示骨髓增生 明显的嗜酸性粒细胞增多。 淋巴瘤对治疗反应良好，但大多数 患者进展为全面的、迅速致命的、急性骨髓性白血病 白血病。 值得注意的是，患有这种综合征的患者具有平衡 相互易位，涉及染色体带 8p11 和 13q11-12， 在淋巴瘤周围淋巴结和骨髓增生性淋巴结中 骨髓细胞。 这一观察表明易位 (8;13) 是 多能细胞中的一个关键的致癌事件能够同时 骨髓和淋巴分化。 我们绘制了易位图 (8;13) 使用分子细胞遗传学方法断点并具有 将 8p 断点定位于 70 kb 细菌人工染色体 （BAC）克隆。 我们的初步 BAC cDNA 筛选研究表明 FGFRI 作为易位的候选基因之一 (;13)。 我们假设 易位 8p 断点处的基因具有致癌性，并且 通过与 13 号染色体长臂上的癌基因并置而激活。 我们将通过评估 t(813) 淋巴瘤的 FGFRI 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 阴性，我们将继续筛选选定的 cDNA 文库以表达 映射到 8p 易位断点区域的序列。 候选人 癌基因将通过序列分析来鉴定，并将用作 t(8;13) 淋巴瘤细胞 cDNA 的 Southern 和 Northern 印迹中的探针 检测 Southern 和/或 Northern 印迹上的重排片段将是 用作锚点来识别 13 号染色体上相应的癌基因， 并且将分离这两个基因的全长cDNA。 的生物学作用 t(8;13) 癌蛋白将在生理学方面进行评估 造血和白血病发生 - 通过体外和体内 泛函分析。