Mouse model of infant acute megakaryocytic leukemia

描述(申请人提供)：大多数非唐氏综合症儿童的婴儿急性巨核细胞白血病(AMKL)有一种独特的染色体易位，t(1；22)。这种易位融合了两个被认为是转录因子的新基因，即OTT(又名。RBM15)和Mal(又名MKL1/MRTF-A/BSAC)，并导致嵌合蛋白的表达。已在已知参与分化、增殖和白血病发生的蛋白质中鉴定出融合内的同源结构基序。为了阐明OTT-Mal融合蛋白诱导的病理生理机制，我们用敲入法建立了OTT-Mal融合蛋白在OTT基因座的表达小鼠。通过表达内源性OTT启动子的融合蛋白，可以重现人类白血病中OTT-Mal的化学计量比和表达模式。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的发生和正常的巨核细胞生成具有关键影响。 鉴定OTT-MAL可能诱发白血病的途径将需要更全面地了解OTT和MAL的组成基因，因为它们的造血作用尚不清楚。在小鼠中OTT或Mal的缺失将为确定OTT-Mal在基因表达和生理方面的失调途径提供宝贵的试剂。将使用常规模型研究OTT-MAL在t(1；22)AMKL中的作用，以解决以下问题： 具体目的1.OTT-Mal在小鼠中的表达有什么后果？ 具体目的2.OTT在体内的生理作用是什么，OTT-MAL融合蛋白利用哪些内源性OTT途径？ 具体目标3.MAL功能在正常生理和OTT-MAL介导的调节失调中起什么作用？ T(1；22)AMKL小鼠模型的建立和分析将为AMKL发病机制的研究、潜在的治疗干预和巨核细胞发育的基础研究提供新的机会。

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.