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）合作的分子和细胞途径，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）创造了一个融合基因CBFB-MYH11，它使小鼠易患AML，但不足以引发白血病的发生。其中一个候选Cbfb-MYH 11合作基因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，我们将在条件Cbfb-MYH1 - 11敲入BXH-2小鼠模型中进行逆转录病毒插入突变筛选。此外，鉴定的候选基因的功能表征将通过体内重组实验来完成，同时进行体外增殖和凋亡分析。通过这些研究，我们将在揭示造血干细胞调节稳态的分子机制方面取得重大进展。此外，阐明与inv（16）相关的AML发展有关的新途径和分子机制将直接有助于理解人类AML的形成，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.