MLL TRANSLOCATIONS IN T-AML

本研究项目将集中于与治疗相关的急性髓系白血病。 11号染色体易位的白血病(t-AML)患者， 银行11q23。这些患者通常有急性单核细胞或 粒单核细胞白血病，也与重排有关 11q23在初治白血病患者中的表达。有趣的是，一个实质性的 部分受累于11q23的t-ALM患者接受了 表鬼臼毒素，依托泊苷(VP16)或替尼平(VM26)，作为部分 他们对一种原发恶性肿瘤的治疗方案。这些药有反应 与DNA拓扑异构酶II(Topo II)结合，并在以下情况下导致染色体断裂 添加到培养细胞中。我们已经克隆了涉及到的MLL基因 在从头开始和治疗相关的11q23易位中都是如此。 我们将研究MLL基因的结构，特别是在MLL中 断点群集区(BCR)，以及其中一个 MLL伴侣基因在t-AML患者中最常见，AF9。我们 将研究AP16是否会导致MLL相对于 其他已知与易位有关但没有关联的基因 有接触过这类药物的人。我们将对 T-AML患者的基因组易位断裂点区域 确定在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会提供一些关于 这些基因组区域对重排的明显敏感性 暴露于TOPO II靶向药物。最后，我们将克隆和分析 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 基因还参与了其他易位。

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.