Mouse model of infant acute megakaryocytic leukemia

描述（由申请人提供）：大多数非唐氏综合征儿童的婴儿急性巨核细胞白血病（AMKL）具有独特的染色体易位t（1;22）。这种易位融合了两个被认为是转录因子的新基因，OTT（又名RBM15）和MAL（又名MKL1/MRTF-A/BSAC），并导致嵌合蛋白的表达。同源结构基序的融合已确定在蛋白质已知参与分化，增殖和白血病的发生。为了阐明OTT- mal融合蛋白诱导的病理生理，我们使用敲入方法从OTT位点产生表达OTT- mal的小鼠。通过表达来自内源性OTT启动子的融合蛋白，可以复制人类白血病中发现的OTT- mal的化学计量和表达模式。不断发展的数据表明，基因剂量和调控的细微差异对白血病发生和正常巨核生成有关键影响。

DESCRIPTION (provided by applicant): The majority of infant acute megakaryocytic leukemias (AMKL) in non-Down Syndrome children have a unique chromosomal translocation, t(1;22). This translocation fuses two novel genes believed to be transcription factors, OTT (a.k.a. RBM15) and MAL (a.k.a. MKL1/MRTF-A/BSAC), and results in the expression of a chimeric protein. Homologous structural motifs within the fusion have been identified in proteins known to be involved in differentiation, proliferation and leukemogenesis. To elucidate the pathophysiology induced by the OTT-MAL fusion protein, mice have been generated using a knock-in approach to express OTT-MAL from the OTT locus. By expressing the fusion protein from the endogenous OTT promoter, the stoichiometry and expression pattern of OTT-MAL found in the human leukemia should be reproduced. Evolving data suggests subtle differences in gene dosage and regulation have a critical impact on leukemogenesis and normal megakaryopoiesis. Identification of the pathways by which OTT-MAL may induce leukemogenesis will require a more comprehensive understanding of the component genes, OTT and MAL as their hematopoietic roles are unknown. Deletion of OTT or MAL in mice will provide an invaluable reagent in defining the pathways dysregulated by OTT-MAL in terms of gene expression and physiology. The role of OTT-MAL in t(1;22) AMKL will be investigated using routine models to address the following questions: Specific Aim 1. What are the consequences of OTT-MAL expression in mice? Specific Aim 2. What is the in vivo physiologic role of OTT and which pathways of endogenous OTT are utilized by the OTT-MAL fusion protein? Specific Aim 3. What role does MAL function have in normal physiology and in OTT-MAL-mediated dysregulation? The establishment and analysis of a murine model of t(1;22) AMKL will provide new opportunities for the study of pathogenesis in AMKL, potential therapeutic interventions and fundamental insight into megakaryocyte development.