MLL TRANSLOCATIONS IN T-AML

本研究项目将重点关注治疗相关的急性髓系白血病 患有11号染色体易位的白血病（t-AML）患者， 银行11 q23. 这些患者通常有急性单核细胞或 骨髓单核细胞白血病，也与 11 q23在初发白血病患者中的作用 有趣的是， 部分11 q23受累的t-ALM患者接受了 表鬼臼毒素，依托泊苷（VP 16）或替尼泊苷（VM 26），作为部分 原发性恶性肿瘤的治疗方案 这些药物会 与DNA拓扑异构酶II（topo II），并导致染色体断裂时， 添加到培养的细胞中。 我们已经克隆了MLL基因， 在新发和治疗相关的11 q23易位中。 我们将研究MLL基因的结构，特别是在MLL 断裂点簇区（BCR），以及其中一个 最常参与t-AML患者的MLL伴侣基因，AF 9。 我们 将研究AP 16是否会导致MLL相对于 其他已知参与易位但不相关的基因 有接触过这类毒品的记录 我们将对 从t-AML患者的基因组易位断裂点区域到 确定在连接处是否存在任何序列基序， 给出关于潜在重组机制的信息。 在一起， 结构和序列的研究可以提供一些见解， 这些基因组区域对重排的明显敏感性， 暴露于拓扑异构酶II靶向药物。 最后，我们将克隆和分析 MLL易位的一个新伙伴，已在两个t- AML患者的t（11;16）（q23;p13），并将确定这是否 基因参与其他易位。

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.