FLT3 GENOTYPES IN ACUTE MYELOID LEUKEMIA

急性髓系白血病中的 FLT3 基因型

• 批准号: 6521734
• 负责人: SUSAN P WHITMAN
• 金额: $ 11.17万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521734
• 关键词: SDS polyacrylamide gel electrophoresis; acute myelogenous leukemia; apoptosis; autoradiography; biological signal transduction; bone marrow transplantation; cell proliferation; clinical research; cytotoxicity; flow cytometry; gene expression; gene mutation; genotype; human tissue; immunocytochemistry; immunoprecipitation; laboratory mouse; neoplasm /cancer immunology; platelet derived growth factor; polymerase chain reaction; protein tyrosine kinase; receptor expression; stem cells; transfection

DESCRIPTION (provided by applicant): Acute leukemia is a malignancy of the hematopoietic elements that results at least in part from inappropriate activation of tyrosine kinases (TK). The most frequent somatic mutation associated with adult acute myeloid leukemia (AML) to date is the internal tandem duplication (ITD) of the FLT3 gene, a member of the Type III PDGF superfamily of receptor TKs. The FLT3 ITD defect results in the constitutive activation of the tyrosine kinase in the absence of ligand binding. Clinical studies thus far, however, have provided contradictory results with regards to presence of FLT3 ITD and prognostic significance of this defect in AML. These inconsistencies may be due to factors known to have confounding prognostic importance, such as varying cytogenetics, age, and treatment regimens. We examined a group of AML patients homogeneous for age, cytogenetics and treatment, and all considered at standard risk for relapse following therapy. We demonstrated three distinct genotypes among 82 patient samples examined: patients homozygous for the wild type (WT) FLT3 gene; patients heterozygous (FLT3ITD/WT), and patients hemizygous, i.e., FLT3 ITD in the absence of the WT gene, or FLT3ITD/-. Only the latter was a highly significant predictor of profoundly worse prognosis in AML patients compared to the others considered at standard risk. The overall research objective outlined in this proposal is to understand the mechanism by which the hemizygous genotype confers an especially poor prognosis, and to target this molecular defect in vitro and in vivo with a FLT3-specific inhibitor. To accomplish this goal, AIM 1 will investigate if a constitutively active mutant FLT3 in the absence of wild-type FLT3 confers a dominant positive gain-of-function role using in vitro and in vivo models. AIM 2 will assess whether proliferation and survival of FLT3 ITD-positive patient AML cells are selectively inhibited via induction of apoptosis by newly developed FLT3 inhibitor compounds. Funding of this K01 Mentored Minority Career Development Award will provide invaluable training for the applicant in the area of molecular mechanisms of disease, animal models for the study of human leukemia, and molecular targeted approaches to cancer therapy.

描述（由申请人提供）：急性白血病是造血元素的恶性肿瘤，至少部分是由于酪氨酸激酶（TK）的不适当激活而产生的。 迄今为止，与成年急性髓样白血病（AML）相关的最常见的体细胞突变是FLT3基因的内部串联重复（ITD），这是受体TKS III型PDGF超级家族的成员。 在没有配体结合的情况下，FLT3 ITD缺陷导致酪氨酸激酶的组成型激活。 然而，迄今为止，临床研究为AML中该缺陷的FLT3 ITD和预后意义提供了矛盾的结果。 这些不一致可能是由于已知的因素具有混乱的重要性，例如不同的细胞遗传学，年龄和治疗方案。 我们检查了一组针对年龄，细胞遗传学和治疗同质的AML患者，所有这些患者都认为治疗后有复发的标准风险。 我们在检查的82例患者样本中展示了三种不同的基因型：野生型（WT）FLT3基因纯合的患者；患者杂合（FLT3ITD/WT）和半合子的患者，即在没有WT基因或FLT3ITD/ - 的情况下，flt3 ITD。 与以标准风险相比，只有后者是AML患者预后较差的预后较差的高度显着预测指标。 该提案中概述的总体研究目标是了解半合子基因型赋予预后特别差的机制，并在体外和体内靶向这种分子缺陷，并具有FLT3特异性抑制剂。 为了实现这一目标，AIM 1将在没有野生型FLT3的情况下研究组成性活跃的突变体FLT3是否会使用体外和体内模型赋予优势积极的功能。 AIM 2将评估FLT3 ITD阳性患者AML细胞的增殖和存活是否通过新开发的FLT3抑制剂化合物诱导凋亡选择性抑制。 这一K01指导的少数族裔职业发展奖的资金将为疾病分子机制，人类白血病研究的动物模型以及分子靶向癌症治疗方法提供宝贵的培训。