Modeling Childhood TEL-AML1 (Runx1)

儿童急性淋巴细胞性白血病(ALL)最常见的遗传实体与 T(12；21)染色体易位导致融合蛋白TEL-AML1/RUNX1的表达 电话号码。流行病逻辑研究表明，TEL-AML1融合是一种体细胞突变 在新生儿中的发病率至少是ALL的10倍。因此，人们认为 还需要其他事件，包括另一个TEL等位基因的功能丧失(如在 多数电话-AML1全部)。目前对儿童ALL的治疗，虽然有效，但都是经验性的 潜在的有毒物质。针对ALL基因损伤的药物治疗提供了降低发病率的可能性 同时保持药效。为了接近这一点，需要一个有效的ALL临床前模型。目标是 这里是在小鼠中建立TEL-AML1白血病模型，该模型准确地反映了白血病的发病机制 天哪。我们已经产生了允许激活TEL-AML1融合的条件突变小鼠品系 来自内源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命中发挥作用。TEL-AML1表达激活导致血管内皮细胞受阻 淋巴细胞生成，c-kit+祖细胞群体扩大，但没有进展为弗兰克白血病。因此， 内源性TEL基因座融合蛋白的表达干扰正常淋巴系 而且似乎会产生“白血病前期”状态。我们目前的目标(1)进一步说明了 TELL-AML1表达小鼠的白血病前表型和扩展的c-kit+群体的特性； (2)确定TELL-AML1表达在造血后期被激活的小鼠的表型， TELL-AML1小鼠与CD2-cre杂交的B淋巴系特异性 小鼠；(3)从(1)和(2)开始对小鼠进行逆转录病毒插入突变，以转化白血病前期 白血病和确定体内互补基因；以及(4)对候选酪氨酸激酶进行功能测试 在项目1中确定用于补充(I)和(2)中的小鼠并在逆转录病毒后产生弗兰克白血病 基因转移。这些研究应该会导致产生准确模拟儿童ALL的小鼠。

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.