MLL TRANSLOCATIONS IN T-AML

T-AML 中的 MLL 易位

• 批准号: 6269194
• 负责人: JANET D ROWLEY
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-05 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269194
• 关键词: acute myelogenous leukemia; artificial chromosomes; chemical carcinogenesis; chimeric proteins; chromosome translocation; clinical research; doxorubicin; drug adverse effect; drug related neoplasm /cancer; etoposide; gene mutation; gene rearrangement; genetic mapping; human genetic material tag; human subject; molecular cloning; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; nucleic acid sequence; oncogenes; oncoproteins; podophyllin

This research project will focus on the therapy-related acute myeloid leukemia (t-AML) patients who have translocations of chromosome 11, bank 11q23. These patients usually have acute monoblastic or myelomonocytic leukemia which is also associated with rearrangements of 11q23 in patients with de novo leukemia. Interestingly, a substantial fraction of the t-ALM patients with 11q23 involvement have received epipodophyllotoxins, either etoposide (VP16) or teniposide (VM26), as part of their treatment regimen for a primary malignancy. These drugs react with DNA topoisomerase II (topo II) and cause chromosome breaks when added to cultured cells. We have cloned the MLL gene that is involved both in the de novo and in the therapy-related 11q23 translocations. We will study the structure of the MLL gene, particularly in the MLL breakpoint cluster region (BCR), as well as the structure of one of the MLL partner genes most commonly involved in t-AML patients, AF9. We will study whether AP16 causes preferential breakage in MLL relative to other genes known to be involved in translocations, but not associated with prior exposure to this class of drugs. We will sequence the genomic translocation breakpoint regions from t-AML patients to determine whether any sequence motifs are present at the junctions, giving information about potential recombination mechanisms. Together, the structure and sequence studies may provide some insights as to the apparent sensitivity of these genomic regions to rearrangement after exposure to topo II targeting drugs. Finally, we will clone and analyze a new partner of MLL translocations that has been identified in two t- AML patients with a t(11;16)(q23;p13), and will determine whether this gene is involved in other translocations.

该研究项目将重点关注与治疗相关的急性髓系细胞 患有 11 号染色体易位的白血病 (t-AML) 患者， 银行 11q23。 这些患者通常患有急性单核细胞或 粒单核细胞白血病也与基因重排有关 新发白血病患者的 11q23。 有趣的是，大量的 11q23 受累的 t-ALM 患者中接受治疗的比例 表鬼臼毒素，依托泊苷 (VP16) 或替尼泊苷 (VM26)，作为一部分 他们针对原发性恶性肿瘤的治疗方案。 这些药物会发生反应 与 DNA 拓扑异构酶 II (topo II) 结合并导致染色体断裂 添加到培养的细胞中。 我们已经克隆了相关的 MLL 基因 无论是从头还是治疗相关的 11q23 易位。 我们将研究MLL基因的结构，特别是MLL 断点簇区域（BCR），以及其中之一的结构 MLL 伴侣基因 AF9 最常参与 t-AML 患者。 我们 将研究 AP16 是否会导致 MLL 相对于 其他已知参与易位但不相关的基因 之前接触过此类药物。 我们将排序 t-AML 患者的基因组易位断点区域 确定连接处是否存在任何序列基序， 提供有关潜在重组机制的信息。 一起， 结构和序列研究可能提供一些关于 这些基因组区域对重排的明显敏感性 暴露于拓扑 II 靶向药物。 最后我们来克隆并分析 MLL 易位的新伙伴已在两个 t- 具有 t(11;16)(q23;p13) 的 AML 患者，并将确定这是否 基因参与其他易位。