Modeling Childhood TEL-AML1 (Runx1)

童年建模 TEL-AML1 (Runx1)

• 批准号: 7058454
• 负责人: STUART H ORKIN
• 金额: $ 12.61万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058454
• 关键词: aging; children; gene mutation; glucocorticoids; model; small molecule; tyrosine

The most common genetic entity in childhood acute lymphoblastic leukemia (ALL) is associated with a t(12;21) chromosomal translocation that leads to expression of the fusion protein TEL-AMLl/runx1 from the TEL locus. Epidemic logical studies demonstrate that the TEL-AML1 fusion is present as a somatic mutation in newborns at a frequency at least 10-fold higher than the incidence of ALL. Hence, it is believed that additional events are required, including loss of function of the other TEL allele (as occurs in the vast majority of TEL-AML1 ALL). Current therapy of childhood ALL, though effective, is empirical and potentially toxic. Drug therapy targeted to genetic lesions in ALL offers the possibility of reducing morbidity while retaining efficacy. In order to approach this, a valid preclinical model of ALL is required. The goal here is to generate a model of TEL-AML1 leukemia in the mouse that accurately reflects the pathogenetics in man. We have generated conditional mutant mouse strains that permit activation of the TEL-AML1 fusion gene from the endogenous TEL locus (hence, at an appropriate expression level) and inactivation of TEL function either during embryogenesis or later in life. Activation of TEL-AML1 expression leads to a block in lymphopoiesis, expansion of a c-kit+ progenitor population, but no progression to frank leukemia. Thus, expression of the fusion protein from the endogenous TEL locus interferes with normal lymphoid development and appears to generate a "preleukemic" state. Our current aims (1) characterize further the preleukemic phenotype and the properties of the expanded c-kit+ population in TEL-AML1 expressing mice; (2) determine the phenotype of mice in which TEL-AML1 expression is activated later in hematopoiesis, specifically within the B-lymphoid lineage by intercrosses of flox-stopped TEL-AML1 mice with CD2-cre mice; (3) perform retroviral insertional mutagenesis in mice from (1) and (2) in order to convert preleukemia to leukemia and identify in vivo complementing genes; and (4) functionally test candidate tyrosine kinases identified in the Project 1 to complement mice in (I) and (2) and generate frank leukemia following retroviral gene transfer. These studies should lead to generation of mice that accurately model childhood ALL.

儿童急性淋巴细胞白血病（ALL）中最常见的遗传实体与 t（12;21）染色体易位，其导致融合蛋白TEL-AML 1/runx 1从所述细胞表达。 TEL轨迹。流行病学研究表明，TEL-AML 1融合是作为体细胞突变存在的 在新生儿中的发生率至少比ALL的发生率高10倍。因此，据信， 需要额外的事件，包括另一个TEL等位基因的功能丧失（如在大部分人中发生的）。 大多数TEL-AML 1 ALL）。目前儿童ALL的治疗虽然有效，但仍是经验性的， 可能有毒针对ALL遗传病变的药物治疗提供了降低发病率的可能性 同时保持功效。为了接近这一点，需要一个有效的ALL临床前模型。目标 本研究旨在建立小鼠TEL-AML 1白血病模型，该模型准确反映了 伙计我们已经产生了允许TEL-AML 1融合激活的条件突变小鼠品系 来自内源性TEL基因座的基因（因此，在适当的表达水平）和TEL的失活 在胚胎发育期间或以后的生活中发挥作用。TEL-AML 1表达的激活导致细胞凋亡的阻断。 淋巴细胞生成，c-kit+祖细胞群扩增，但没有进展为弗兰克白血病。因此，在本发明中， 来自内源性TEL基因座的融合蛋白的表达干扰了正常淋巴细胞的增殖。 发展并似乎产生“白血病前期”状态。我们目前的目标（1）进一步描述 表达TEL-AML 1的小鼠中的白血病前表型和扩增的c-kit+群体的性质; (2)确定TEL-AML 1表达在造血后期被激活的小鼠的表型， 特别是在B淋巴细胞系中，通过将CD 2-cre阻断的TEL-AML 1小鼠与CD 2-cre交叉， 小鼠;（3）在来自（1）和（2）的小鼠中进行逆转录病毒插入诱变以转化白血病前期 白血病和鉴定体内互补基因;和（4）功能测试候选酪氨酸激酶 在项目1中鉴定的，以补充（I）和（2）中的小鼠，并在逆转录病毒后产生明显的白血病 基因转移。这些研究应该导致产生准确模拟儿童ALL的小鼠。