Genetic Dissection of Tumor Progression in NF-1 AML

描述：（由申请人提供）青少年粒单核细胞白血病（JMML）是 一种发生在幼儿身上的疾病，死亡率很高 率在大多数患者中，JMML具有导致死亡的进行性过程， 由于感染、出血或进展为急性髓性白血病（AML）。 众所周知，患有1型神经纤维瘤病（NF 1）的儿童具有 显著增加了患JMML的风险，我们能够培养出一只小鼠， 造血干细胞重建致死性照射小鼠JMML模型 对于Nfl基因中的功能缺失突变纯合的细胞。过程中 在这些实验中，我们发现所有这些基因相同的 重组小鼠出现了JMML样疾病，但只有一部分小鼠继续发展， 患上更严重的疾病。这一结果有力地表明， 遗传损伤是疾病进展的原因。的重点 建议是确定这些额外的遗传病变，作为一种手段， 了解白血病的进展为了实现这一目标，我们将Nf 1 BXH-2小鼠遗传背景上的突变，一种已知含有 体细胞感染嗜亲性逆转录病毒。利用这种强大的躯体 突变系统，我们已经确定了三个共同的亲嗜性前病毒 整合（Epi）位点。我们假设这些肾上腺素位点 鉴定参与骨髓肿瘤进展的基因。我们有 四个具体目标：具体目标1：确定病毒是否整合在Epil 该位点导致c-myb基因的失调。 具体目标2：表征在基因组中被病毒整合中断的基因。 Epi 2基因座。 具体目标3：表征在基因组中被病毒整合中断的基因。 Epi 3基因座。 具体目标4：确定参与肿瘤进展的其他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.