GENETIC ANALYSIS OF A FAMILIAL LEUKEMIA SYNDROME

尽管在过去的3年里白血病的治疗取得了显著的进展， 几十年来，大多数成年白血病患者死于 疾病或治疗的并发症。 有令人信服的证据 白血病和人类其他癌症一样， 多重突变 虽然在这方面取得了重大进展， 对白血病发病机制中涉及的基因的鉴定 在过去的十年里，人们对地球上的初始事件知之甚少。 白血病的发病机制。 我们对早期的理解不足 白血病的分子发病机制中的事件部分是由于 罕见的白血病家族易感性。 与癌症相比， 例如乳腺癌和结肠癌，其中遗传性癌症 遗传易感性允许连锁分析和定位克隆 在生殖系中传播的“第一次打击”突变中， 白血病倾向的家庭，这将允许一个类似的方法。 然而，我们已经确定了一个扩展的谱系，其特征是 易患白血病 此外，该特征是“标记”的。 由于血小板缺陷， 识别受影响的个人。 这项提案的目的是 来确定导致这种遗传性白血病的基因 综合征，这反过来可能提供有关早期 白血病发病机制中的遗传事件。 使用广义连锁方法，我们已经定位了 导致白血病的遗传易感性， 人类染色体21q22.1。 此外，我们最近发现了一个 具有相同临床表型的第二个家系，其也证明 与染色体21q22.1连锁。因此，有确凿的证据表明， 表明该位点与遗传性白血病发病机制有关。 目标 这项建议的目的是确定负责 家族性血小板疾病，有发展AML的倾向。 我们 如提案正文所述， 对该区域的基因进行突变分析。 基于 根据其他遗传性癌症的经验，我们可以预测， FPD疾病基因的突变也与散发性 白血病，并将提供有价值的信息， 白血病中的事件。 反过来，这些信息可以提供洞察力， 治疗白血病的新治疗方法。

Despite remarkable advances in therapy of leukemia over the past 3 decades, the majority of adult patients with leukemia die from complications of their disease or therapy. There is convincing evidence that leukemia, like other cancers in humans, is the consequence of multiple mutations. Although significant strides have been made in identification of genes implicated in pathogenesis of leukemia over the past decade, little is known about the initiating events in the pathogenesis of leukemia. The deficit in our understanding of the early events in the molecular pathogenesis of leukemia is due in part to the rarity of familial predisposition to leukemia. In contrast with cancers such as breast and colon cancer, in which an inherited cancer predisposition has allowed for linkage analysis and positional cloning of the "first hit" mutations transmitted in the germline, there are few leukemia-prone families that would allow for an analogous approach. However, we have identified an extended pedigree characterized by a predisposition to develop leukemia. Furthermore, the trait is "marked" at birth by a platelet defect that has allowed for reliable identification of affected individuals. The goal of this proposal is to identify the gene that is responsible for this inherited leukemia syndrome, which in turn may provide critical information about the early genetic events in the pathogenesis of leukemia. Using a generalized linkage approach, we have localized the gene that causes the inherited predisposition to leukemia to a small region of human chromosome 21q22.1. In addition, we have recently identified a second pedigree with the same clinical phenotype which also demonstrates linkage to chromosome 21q22.1. Thus, there is convincing evidence to implicate this locus in pathogenesis of inherited leukemias. The goal of this proposal is to identify the gene which is responsible for the familial platelet disorder with propensity to develop AML. Our approach, as detailed in the body of the proposal, will focus on mutational analysis of genes which map to this region. Based on experience with other inherited cancers, we would predict that mutations in the FPD disease gene will also be relevant in sporadic leukemias, and will provide valuable information about the early genetic events in leukemia. In turn, this information may provide insight into novel therapeutic approaches to treatment of leukemia.