Inv(16) mediated acute myeloid leukemia in mouse models

描述（由申请人提供）：本提案的目的是了解与inv（16）（在人类急性髓性白血病（AML）中发现的最常见的染色体突变之一）合作的分子和细胞途径。 Inv（16）创建了一个融合基因CBFB-MYH 11，该基因使小鼠易患AML，但不足以触发白血病发生。 候选Cbfb-MYH 11协作基因之一Runx 2将在造血和AML中进行功能表征。 为了进一步鉴定Cbfb-MYH 11协同基因，将在条件性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，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所鉴定的候选基因的功能表征。 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，对inv（16）相关AML发展中涉及的新途径和分子机制的阐明将直接有益于对人类AML形成的理解，并为开发新的治疗方法提供线索。

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.