Molecular Genetic Changes in Leukemia in Infants

描述(申请人提供)：MLL基因易位 许多伴侣基因与临床侵袭性白血病有关 婴儿。这项工作的目的是了解病原学和 这些移位的后果。基因组断裂点序列表明 DNA损伤参与了移位过程，但病原学 经纪人(S)不明。失活的NQO1基因多态赋予基因 被NQO1解毒的苯醌的敏感性和DNA损伤， 可能干扰DNA拓扑异构酶II。第一种假设是DNA 拓扑异构酶II介导导致易位的染色体断裂， 苯二酚导致了断裂，并形成了移位 当破损被修复后。第二个假设是基因表达 反映初级和次级分子变化的模式将随 性伴基因并影响生物学和预后。AIM I检查DER(11) 和DER(其他)断点连接序列，以寻找关联的证据 具有特定损伤模式的NQO1基因。这些实验将证明 受损伤和狭长柄PCR方法影响的序列基序将 很容易产生新的伴侣基因。目标2和目标3结合了分子生物学， 生物化学和质谱学方法研究白纹伊蚊基因组断裂点序列 细胞和体外模型系统。测定苯二酚是否 DNA拓扑异构酶II依赖的基因组断裂点序列的损伤 方式和特征的损害的性质解决的病因 问题。如果第一个假设是正确的，结果可能会显示出具体的 与苯醌相关的损伤，导致易位。AIM 4用途 利用寡核苷酸芯片研究不同配对基因对基因的影响 表情模式。配对基因hCDCre1和SEPTIN2是a成员 婴幼儿AML涉及不同的基因家族。AIM 5利用逆转录病毒基因 转移研究MLL-Septin融合蛋白在小鼠体内的转化能力 同基因小鼠。如果第二个假设是正确的，各种MLL的白血病 易位将可以通过它们的基因表达模式来区分。这 多学科研究计划阐明该病的病因和后果 MLL易位可能为治疗和预防提供新的方法。

DESCRIPTION (provided by applicant): Translocations of the MLL gene with one of many partner genes are associated with clinically aggressive leukemias in infants. The objective of this work is to understand the etiology and consequences of these translocations. The genomic breakpoint sequences suggest that DNA damage is involved in the translocation process but the etiologic agent(s) is unknown. An inactivating NQO1 polymorphism confers genetic susceptibility and DNA damage from benzoquinone, which is detoxified by NQO1, may interfere with DNA topoisomerase II. The first hypothesis is that DNA topoisomerase II mediates chromosomal breakage that results in translocations, that benzoquinone contributes to the breakage, and that translocations form when the breakage is repaired. The second hypothesis is that gene expression patterns reflecting primary and secondary molecular alterations will vary with the partner gene and affect biology and prognosis. Aim I examines the der(1l) and der(other) breakpoint junction sequences for evidence of associations of NQO1 genotypes with specific damage patterns. These experiments will show the sequence motifs affected by the damage and the panhandle PCR approaches will lead readily to new partner genes. Aims 2 and 3 combine molecular biology, biochemistry and mass spectrometry to study the genomic breakpoint sequences in cellular and in vitro model systems. Assays to determine whether benzoquinone damages the genomic breakpoint sequences in a DNA topoisomerase II dependent manner and to characterize the nature of the damage address the etiologic question. If the first hypothesis is correct, the results may show specific benzoquinone-related damage that leads to translocations. Aim 4 uses oligonucleotide arrays to discern effects of different partner genes on gene expression patterns. The partner genes hCDCrel and SEPTIN2 are members a distinct gene family involved in infant AML. Aim 5 exploits retroviral gene transfer to investigate the transforming capabilities of MLL-SEPTIN fusions in syngeneic mice. If the second hypothesis is correct, leukemias with various MLL translocations will be distinguishable by their gene expression patterns. This multidisciplinary research plan to elucidate the etiology and consequences of MLL translocations may inform new approaches to treatment and prevention.