RUNX1 gene dosage and cooperativity in leukemia

描述（由申请人提供）：本提案的中心假设是 影响基因剂量的突变和基因重排 造血转录因子RUNXI协同激活突变， FLT3、KIT和RAS引起急性髓系白血病。在过去的融资中 在此期间，我们使用了位置克隆策略来证明 造血转录因子R UNXI的突变 家族性血小板疾病有发展为急性骨髓性的倾向 白血病（FPDIAML综合征，MIM 601399）。随后，我们和其他人 RUNXI在散发性病例中表现出类似的功能丧失突变， 急性髓细胞白血病几个FPD/AML家系的分析支持 RUNXI的单倍不足是FPD/AML综合征的原因。但在 在散发性白血病病例中，RUNXI的两个等位基因都可能发生突变，表明 RUNXI功能的完全丧失可能导致AML进展。 此外，几个AML家系和散发病例携带RUNXI突变， 这可能是部分功能性的或具有转显性效应。反对这个 在此背景下，最近已经认识到，增加RUNX的剂量可以 也有助于造血肿瘤的发病机制。在这一提议中， 我们将探讨RUNX]剂量效应在人类肿瘤发病机制中的作用。 白血病我们预计这种分析将是困难的，部分原因是 大量的证据表明，尽管RUNX1的突变和基因重排 在白血病中常见，但这些都不足以引起AML。我们 认为影响RUNX I剂量的突变可能损害造血功能， 分化，但额外的突变将需要赋予 增殖和/或存活的优势。我们已经证明 FLT3和c-KIT受体酪氨酸中存在激活突变 激酶，K-RAS，与RUNX1点相关的人类白血病 突变根据这些观察，我们将继续进行以下具体工作： 目的：1.研究Runxl功能丧失或获得的致白血病性 在老鼠; 2。表征活化突变的白血病潜能， 使用鼠模型的造血受体酪氨酸激酶和K-RAS;和3. 表征FLT3、KIT和K-RAS中激活突变之间的协同性 在白血病发生的鼠模型中具有影响Runxl基因剂量的突变。

DESCRIPTION (provided by applicant): The central hypothesis of this proposal is that mutations and gene rearrangements that affect gene dosage of the hematopoietic transcription factor RUNXI cooperate with activating mutations in FLT3, KIT and RAS to cause acute myeloid leukemia. During the previous funding period for this proposal, we used a positional cloning strategy to demonstrate that mutations in the hematopoietic transcription factor R UNXI are responsible for the familial platelet disorder with propensity to develop acute myeloid leukemia (FPDIAML syndrome, MIM 601399). Subsequently, we and others have demonstrated similar loss of function mutations in RUNXI in sporadic cases of acute myeloid leukemia. Analysis of several FPD/AML pedigrees supports haploinsufficiency of R UNXI as the cause of the FPD/AML syndrome. However, in sporadic cases of leukemia, both alleles of R UNXI may be mutated, indicating that complete loss of function of RUNXI may contribute to progression to AML. In addition, several pedigrees and sporadic cases of AML harbor RUNXI mutations that may be partially functional or have transdominant effects. Against this backdrop, it has recently been appreciated that increased dosage of RUNX] may also contribute to pathogenesis of hematopoietic neoplasia. In this proposal, we will explore the role of RUNX] dosage effects in the pathogenesis of human leukemia. We anticipated that this analysis would be difficult, in part because of abundant evidence that, although mutations and gene rearrangements of RUNX1 are frequent in leukemia, none of these are sufficient to cause AML. We reasoned that mutations affecting RUNX I dosage may impair hematopoietic differentation, but that additional mutations would be required to confer proliferative and/or survival advantage to these cells. We have demonstrated the presence of activating mutations in the FLT3 and c-KIT receptor tyrosine kinases, and in K-RAS, in human leukemias associated with RUNX1 point mutations. Based on these observations we will pursue the following Specific Aims: 1.Characterize the leukemogenicity of loss or gain of function of Runxl in the mouse; 2. Characterize leukemic potential of activating mutations in hematopoietic receptor tyrosine kinases and K-RAS using murine models; and 3. Characterize cooperativity between activating mutations in FLT3, KIT and K-RAS with mutations affecting Runxl gene dosage in murine models of leukemogenesis.