Genetic Dissection of Tumor Progression in NF-1 AML

描述：(申请人提供)青少年粒单核细胞白血病(JMML)是 一种发生在幼儿中的疾病，与高死亡率有关 费率。在大多数患者中，JMML有一个渐进的病程，通过 感染、出血或进展为急性髓系白血病(AML)的优点。 众所周知，患有1型神经纤维瘤病(NF1)的儿童有一种 患JMML的风险显著增加，我们能够开发出一种小鼠 用造血干细胞重建致死性照射小鼠的JMML模型 NFL基因功能缺失突变的纯合子细胞。在课程中 在这些实验中，我们发现所有这些基因上相同的 重组的小鼠出现了一种类似JMML的疾病，但只有一小部分继续 发展出更多的急性疾病。这一结果有力地表明， 基因损伤是疾病进展的原因。这件事的重点是 建议确定这些额外的遗传损伤作为一种更好的手段 了解白血病的进展情况。为了实现这一目标，我们将NF1 BXH-2小鼠遗传背景上的突变，一种已知含有 具有躯体感染性的嗜生态逆转录病毒。利用这种强大的体细胞 突变系统，我们鉴定了三种常见的生态型前病毒 整合(EPI)站点。我们假设这些EPI站点将允许 鉴定与髓系肿瘤进展有关的基因。我们有 四个具体目标：具体目标1：确定病毒在EPIL中的整合 位点导致c-myb基因的失控。 特定目标2：确定被病毒整合中断的基因 Epi2基因座。 具体目标3：确定被病毒整合中断的基因 Ep3基因座。 具体目标4：确定更多与肿瘤进展有关的EPI位点 JMML。

DESCRIPTION: (provided by applicant) Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding or progression to acute myeloid leukemia (AML). As it is known that children with Neurofibromatosis type 1 (NF1) have a markedly increased risk of developing JMML, we were able to develop a mouse model of JMML by reconstituting lethally irradiated mice with hematopoetic stem cells homozygous for a loss of function mutation in the Nfl gene. In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression. The focus of this proposal is to identify these additional genetic lesions as a means to better understand leukemic progression. Toward this goal, we have placed the Nf1 mutation on the BXH-2 mouse genetic background, a strain known to contain a somatically infectious ecotropic retrovirus. Using this powerful somatic mutagenesis system, we have identified three common ecotropic proviral integration (Epi) sites. We hypothesize that these Epi sites will allow identification of genes that are involved in myeloid tumor progression. We have four specific aims: Specific Aim 1:Determine if viral integration at the Epil site leads to deregulation of the c-myb gene. Specific Aim 2:Characterize the gene interrupted by viral integrations at the Epi2 locus. Specific Aim 3: Characterize the gene interrupted by viral integrations at the Epi3 locus. Specific Aim 4: Identify additional Epi sites involved in tumor progression of JMML.