Genetic Progression Events in Murine APL

描述（由申请人提供）：该提案旨在将候选人在血液学/肿瘤学和分子生物学方面的丰富临床经验结合起来，并允许研究者成功过渡到独立的医师-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，以促进该候选人成为学术医疗中心独立调查员的长期目标。

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.