MOLECULAR-CYTOGENETIC ANALYSIS OF CHROMOSOMES 5 & 7 IN MYELOID DISORDERS

治疗相关骨髓增生异常综合征(t-MDS)或急性髓系 白血病(t-AML)是两者细胞毒治疗的晚期并发症。 恶性和非恶性疾病。特征重现 5号和/或7号染色体的异常常见于t- MDS/t-AML。在我们更新的系列中，我们观察到整个 5或7号染色体，或[del(5q)/del(7q)]的长臂缺失 246例患者中175例(71%)接受检查。在之前的授权期内，我们 描绘了5q31条带内缺失的5号染色体片段 在所有接受检查的患者中，并准备了细胞遗传学图谱和 共同缺失片段的部分基因组重叠群。我们假设 位于该片段中的肿瘤抑制基因可能起作用 在这种疾病的发病机制中起着重要作用。我们现在建议使用 定位克隆和候选基因方法鉴定一种髓系细胞 白血病基因5q31。第一步将是完成 共同缺失片段的基因组重叠群(间隔3-4MB IL9和D5S166)。将使用几种实验方法来 中搜索以前未识别的表达序列 重叠群。以5号染色体异常为特征的白血病细胞 将被检查这些候选基因的突变。如果突变 如果5q上的一个基因被鉴定出来，我们将确定 髓系白血病细胞中的突变，决定了 基因是体细胞还是生殖系，并识别(S)的后果 基因/蛋白质功能上的突变。我们计划划定 利用细胞遗传学作图技术获得7q的最小缺失片段 检测7q基因缺失或易位的白血病细胞。这些 这些研究将为进一步的分子研究奠定基础，以分离出一种 髓系白血病相关基因7q。 肿瘤抑制基因还没有得到很好的表征。 血液系统恶性疾病。我们希望通过分析反复出现的 缺失，我们就可以开始评估隐性突变在 MDS与AML的发病机制及与AML的关系 5号染色体基因突变的细胞毒治疗研究进展 和7.

Therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) is a late complication of cytotoxic therapy of both malignant and non-malignant disease. Characteristic recurring abnormalities of chromosomes 5 and/or 7 are frequently noted in t- MDS/t-AML. In our updated series, we observed loss of an entire chromosome 5 or 7, or a deletion of the long arm of [del(5q)/del(7q)] in 175 of 246 (71%) patients examined. In the previous grant period, we delineated a segment of chromosome 5 within band 5q31 that was deleted in all patients examined, and have prepared a cytogenetic map and partial genomic contig of the commonly deleted segment. We hypothesize that a tumor suppressor gene located within this segment may play r role in the pathogenesis of this disease. We now propose to use a positional cloning and candidate gene approach to identify a myeloid- leukemia gene in 5q31. The initial step will be the completion of the genomic contig of the commonly deleted segment (3-4MB interval between IL9 and D5S166). Several experimental approaches will be used to search for previously unidentified expressed sequences within the contig. Leukemia cells characterized by abnormalities of chromosome 5 will be examined for mutations of these candidate genes. If mutations of a gene on 5q are identified, we will determine the spectrum of mutations in myeloid leukemia cells, determine whether mutations of the gene are somatic or germline, and identify the consequence(s) of the mutations on the function of the gene/protein. We plan to delineate the smallest deleted segment of 7q by using cytogenetic mapping techniques to examine leukemia cells with deletions or translocations of 7q. These studies will form the basis for additional molecular studies to isolate a myeloid leukemia-related gene on 7q. Tumor suppressor genes have not been well-characterized in the hematologic malignant diseases. We hope that by analyzing recurring deletions, we can begin to evaluate the role of recessive mutations in the pathogenesis of MDS and AML, and to elucidate the relationship of previous cytotoxic therapy with mutations of genes on chromosomes 5 and 7.