BACKTRACKING TRANSLOCATIONS IN CHILDHOOD LEUKEMIA

描述(申请人提供)：白血病是儿童中最常见的癌症，也是发病率、压力和长期后遗症的重要原因。尽管在治疗方面取得了进步，可以治愈大多数白血病，但我们对这种疾病的病因仍然知之甚少，阻碍了任何预防的尝试。我们的重点是详细描述白血病中发生的染色体和突变变化，并利用这些遗传异常开发工具来研究这些事件的时机和因果关系。到目前为止，我们一直专注于易位，发现大多数但不是所有易位亚型都起源于子宫内。最常见的儿童期易位，t(12；21)tel-AML1，发生在25%的儿童急性淋巴细胞白血病中，通常发生在出生前，这些儿童后来患上了这种基因突变的白血病。我们现在建议描述TEL-AMLI+白血病的继发遗传事件，首先集中在12P缺失，这是TEL-AMLI+白血病中常见的(~75%)事件。我们将使用阵列比较基因组杂交(ARRAY-CGH)来定义12P染色体缺失的确切断裂点，从而允许在基因组核苷酸水平上克隆它们。下一步，我们将使用克隆的融合点作为探针，通过搜索来自我们也已经测序的相同儿童的新生儿脚后跟穿刺格思里卡上是否存在这种遗传标记来“追溯”白血病的出生，我们也已经对基因组TEL-AML 1易位序列进行了测序和“回溯”。第三，我们将使用12P缺失和TEL-AML1易位来追踪白血病克隆在治疗后在儿童中的命运，从而完成这些基因组融合的“自然历史”的故事，并确定新标记的临床用途。最后，我们将评估可能的肿瘤抑制等位基因(S)的存在，这些等位基因在阵列-CGH实验中被指示为等位基因丢失。初步结果表明，在一些患者中，12P上存在不止一个不同的缺失，这表明了这一分析的复杂性和发现潜力。我们的结果将为北加州儿童白血病研究提供信息和指导，这是一个流行病学项目，我们所有的样本都是从这个项目中得出的。我们最终致力于阐明一种可能可以预防的癌症的起源和原因。

DESCRIPTION (provided by applicant): Leukemia is the most common cancer among children and a significant cause of morbidity, stress, and long-term sequelae. Despite advances in treatment that permit a cure in the majority of leukemias, we still know very little about the causes of the disease, thwarting any attempt at prevention. Our focus is to describe in molecular detail the chromosomal and mutational changes that occur in leukemias, and use these genetic aberrations to develop tools to study the timing and causality of these events. Hitherto we have focused on translocations, finding that most but not all translocation subtypes have an in utero origin. The most common childhood translocation, t(12;21) TEL-AML1, occurs in 25% of childhood acute lymphocytic leukemia and usually, if not always, occurs before birth in children who later contract leukemia with this genetic aberration. We now propose to describe the secondary genetic events in TEL-AMLI+ leukemia, focusing first on the 12p deletion, which is a common (~75%) event in TEL-AMLI+ leukemia. We will use array-Comparative Genomic Hybridization (array-CGH) to define the exact breakpoints of 12p chromosomal deletions, allowing their cloning at the genomic nucleotide level. Next, we will use the cloned fusion junction as a probe to "backtrack" leukemia to birth, by searching for the presence of this genetic marker on neonatal heel-prick Guthrie cards from the same children that we have also sequenced and "backtracked" the genomic TEL-AML 1 translocation sequence. Thirdly, we will use 12p deletions along with TEL-AML 1 translocations to track the fate of the leukemia clone in children after therapy, thereby completing the story of the "natural history" of these genomic fusions and determining clinical utility of the novel markers. Lastly, we will assess the presence of putative tumor suppressor allele(s) that are indicated as allelic loss in array-CGH experiments. Preliminary results suggest the presence of more than one distinct deletion on 12p in some patients, demonstrating the complexity and discovery potential of this analysis. Our results will inform and guide the Northern California Childhood Leukemia Study, an epidemiological project from which all of our samples are derived. We are ultimately working to elucidate the origin and causes of a cancer that might be preventable.