Inv(16) mediated acute myeloid leukemia in mouse models

Inv(16)介导的小鼠模型中的急性髓系白血病

• 批准号: 6739519
• 负责人: YA-HUEI KUO
• 金额: $ 4.73万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739519
• 关键词: acute myelogenous leukemia; apoptosis; carcinogenesis; cell proliferation; cellular oncology; chromosome inversion; disease /disorder model; fusion gene; gene expression; gene interaction; genetically modified animals; hematopoiesis; hematopoietic stem cells; laboratory mouse; molecular oncology; neoplasm /cancer genetics; postdoctoral investigator; site directed mutagenesis

DESCRIPTION (provided by applicant): The objectives of this proposal are to understand the molecular and cellular pathways that cooperate with inv(16), one of the most common chromosomal mutations found in human acute myeloid leukemia (AML). Inv(16) creates a fusion gene CBFB-MYH11, which predisposes mice to AML but is not sufficient to trigger leukemogenesis. One of the candidate Cbfb-MYH 11 cooperating genes, Runx2, will be functionally characterized in hematopoiesis and AML. To further identify Cbfb-MYH1 1 cooperating genes, retrovirus insertional mutagenesis screen in conditional Cbfb-MYH 11 knock-in BXH-2 mouse model will be carried out. Furthermore, functional characterization of the identified candidate genes will be accomplished by reconstitution experiments in vivo in parallel to in vitro proliferation and apoptosis analyses. Through these studies, we will make major progress in revealing the molecular mechanisms in regulating homeostasis of hematopoietic stem cells. Moreover, the elucidation of novel pathways and the molecular mechanisms implicated in inv(16) associated AML development will directly benefit the understanding of AML formation in humans and shed light on the development of novel therapeutic approaches.

描述（由申请人提供）：本提案的目的是了解与 inv(16) 配合的分子和细胞途径，inv(16) 是人类急性髓性白血病 (AML) 中最常见的染色体突变之一。 Inv(16) 产生了一个融合基因 CBFB-MYH11，该基因使小鼠易患 AML，但不足以引发白血病发生。 候选 Cbfb-MYH 11 合作基因之一 Runx2 将在造血和 AML 中进行功能表征。 为了进一步鉴定Cbfb-MYH1 1协同基因，将在条件Cbfb-MYH 11敲入BXH-2小鼠模型中进行逆转录病毒插入诱变筛选。 此外，所鉴定的候选基因的功能表征将通过与体外增殖和凋亡分析平行的体内重建实验来完成。 通过这些研究，我们将在揭示造血干细胞稳态调节的分子机制方面取得重大进展。 此外，阐明与inv(16)相关的AML发展相关的新途径和分子机制将直接有利于对人类AML形成的理解，并为新治疗方法的开发提供线索。