Genetic Progression Events in Murine APL

描述(申请人提供)：这项建议旨在将候选人在血液学/肿瘤学方面的丰富临床经验与分子生物学结合起来，并允许研究人员成功地过渡到独立的内科科学家。这项工作将在Timothy Ley博士的监督下进行，他的实验室在白血病遗传学、转基因技术和小鼠造血分析方面拥有丰富的经验。一个由国家认可的实验血液学家组成的咨询委员会已经成立，以提供科学和职业建议。华盛顿大学癌症中心的核心设施，加上医学院和巴恩斯-犹太医院的科学和临床资源，将提供丰富的环境，促进这位候选人成为学术医学中心独立研究员的长期目标。 这项工作的目的是确定2号染色体[del(2)]上的间质缺失对小鼠急性早幼粒细胞白血病(APL)进展的重要性。为了实现这一目标，我们将在小鼠身上重建2号染色体缺失，并研究其对白血病进展的影响。四个独立的小鼠APL和AML模型获得了del(2)，暗示del(2)是小鼠AML进展中的一个重要事件。此外，高达14%的复发APL患者在人类11号染色体上发生缺失或易位，该染色体与小鼠的del(2)区域同线。因此，在小鼠del(2)模型中了解白血病进展的机制可能有助于在具有相似染色体变化的人类中研究AML和MDS。 在这项建议中，我们将评估del(2)在AML进展中的重要性，方法是使用同源重组和Cre/loxP技术创建del(2)小鼠，并分析这些小鼠的表型(特定目标1)。我们将来自特定目标1的del(2)小鼠与hCG-PML-RAR(小鼠)杂交，并研究与白血病进展相关的机制(特定目标2)。我们将通过评估交叉小鼠出现的白血病的潜伏期、外显率和表型来表征del(2)对AML进展的重要性。我们将系统地评估这些小鼠的造血功能，并研究与白血病进展相关的潜在机制。

DESCRIPTION (provided by applicant): This proposal is designed to combine the candidate's strong clinical experience in hematology/oncology with molecular biology, and allow for the successful transition of the investigator to an independent physician-scientist. This work will be conducted under the supervision of Dr. Timothy Ley, whose laboratory has considerable experience in leukemia genetics, transgenic technology, and analysis of murine hematopoiesis. An advisory committee consisting of nationally recognized experimental hematologist has been assembled to provide scientific and career advice. Core facilities of the Washington University Cancer Center, in addition to the scientific and clinical resources of the School of Medicine and Barnes-Jewish Hospital, will provide a rich environment to facilitate this candidate's long-term goal to become an independent investigator at an academic medical center. The goal of this work is to define the importance of an interstitial deletion on chromosome 2 [del(2)] for the progression of murine acute promyelocytic leukemia (APL). To accomplish this goal, we will recreate the chromosome 2 deletion in the mouse, and study the effect on leukemia progression. Four independent murine APL and AML models acquire del(2), implicating del(2) as an important event in murine AML progression. In addition, up to 14% of relapsed APL patients develop a deletion or translocation on human chromosome 11, syntenic to the mouse del(2) region. Therefore, understanding the mechanism of leukemia progression in murine del(2) models will likely aid the investigation of AML and MDS in humans with similar chromosomal changes. In this proposal, we will assess the importance of del(2) for AML progression by creating mice with del(2) using homologous recombination and Cre/loxP technology, and analyze the phenotype of these mice (Specific Aim 1). We will intercross del(2) mice from Specific Aim 1 with hCG-PML-RAR( mice, and investigate the mechanisms associated with leukemia progression (Specific Aim 2). We will characterize the importance of del(2) for AML progression by evaluating the latency, penetrance, and phenotype of leukemias arising in intercrossed mice. We will systematically evaluate the hematopoiesis of these mice and investigate potential mechanisms associated with leukemia progression.