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协同激活基因突变 Flt3、Kit和RAS可引起急性髓系白血病。在之前的资助期间 期间，我们使用了位置克隆策略来演示 造血转录因子R UNXI的突变是 治疗有急性髓系白血病倾向的家族性血小板疾病 白血病(FPDIAML综合征，MIM 601399)。随后，我们和其他人 散发性黑色素瘤患者RUNXI基因功能突变的类似缺失 急性髓系白血病。几个FPD/AML家系支持的分析 RUNXI单倍体功能不全是FPD/AML综合征的原因。但是，在 散发性白血病，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急性髓系白血病的进展。 此外，几个AML家系和零星病例存在RUNXI突变 这可能部分是功能性的，也可能是具有跨显性效应的。反对这一点 背景：最近人们认识到，增加RUNX的剂量可能 也参与了造血肿瘤的发病机制。在这份提案中， 我们将探索RUNX]剂量效应在人类发病机制中的作用 白血病。我们预计这种分析会很困难，部分原因是 大量证据表明，尽管RUNX1的突变和基因重排 在白血病中很常见，但这些都不足以引起AML。我们 推测影响RUNX I剂量的突变可能会损害造血 差异，但需要额外的突变才能赋予 对这些细胞具有增殖和/或存活优势。我们已经证明了 Flt3和c-kit受体酪氨酸激活突变的存在 与RUNX1点相关的人类白血病中的激酶和K-RAS 突变。基于这些观察，我们将采取以下具体措施 目的：1.研究Runxl功能丧失或获得的白血病原性 在小鼠中；2.表征白血病激活基因突变的潜力 用小鼠模型研究造血细胞受体酪氨酸激酶和K-RAS； Flt3、Kit和K-RAS激活突变之间的协同作用 突变影响白血病小鼠模型中Runx1基因的剂量。

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.