Mouse model of infant acute megakaryocytic leukemia

婴儿急性巨核细胞白血病小鼠模型

• 批准号: 7563228
• 负责人: Glen D Raffel
• 金额: $ 13.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563228
• 关键词: Acute Megakaryocytic Leukemias; Address; Affect; Alleles; Cells; Child; Chimeric Proteins; Chromosomal translocation; Complement; Data; Development; Disease; Down Syndrome; Fibrinogen; Functional disorder; Gene Components; Gene Dosage; Gene Expression; Genes; Hematopoiesis; Hematopoietic; Human; In Vitro; Infant; Knock-in Mouse; Knock-out; Knockout Mice; Mediating; Megakaryocyte Proliferation; Megakaryocytes; Megakaryocytopoieses; Modeling; Molecular; Mus; Mutate; Pathogenesis; Pathway interactions; Pattern; Phenotype; Physiological; Physiology; Preparation; Property; Proteins; Reagent; Regulation; Role; Therapeutic Intervention; in vivo; insight; leukemia; leukemogenesis; mouse model; novel; overexpression; promoter; stoichiometry; transcription factor

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.

描述（由申请人提供）：大多数非唐氏综合症儿童的婴儿急性巨核细胞白血病 (AMKL) 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。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学，使用敲入方法产生了从 OTT 基因座表达 OTT-MAL 的小鼠。通过从内源性 OTT 启动子表达融合蛋白，可以重现人类白血病中发现的 OTT-MAL 的化学计量和表达模式。不断变化的数据表明，基因剂量和调控的细微差异对白血病发生和正常巨核细胞生成具有至关重要的影响。 鉴定 OTT-MAL 可能诱导白血病发生的途径需要对组成基因 OTT 和 MAL 进行更全面的了解，因为它们的造血作用尚不清楚。小鼠中 OTT 或 MAL 的缺失将为定义 OTT-MAL 在基因表达和生理学方面失调的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： 具体目标 1. OTT-MAL 在小鼠中表达有何后果？ 具体目标 2. OTT 的体内生理作用是什么？OTT-MAL 融合蛋白利用内源性 OTT 的哪些途径？ 具体目标 3. MAL 功能在正常生理和 OTT-MAL 介导的失调中起什么作用？ t(1;22) AMKL 小鼠模型的建立和分析将为 AMKL 发病机制、潜在治疗干预措施和巨核细胞发育的基本见解的研究提供新的机会。

项目成果

Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress.

缺乏 Ott1 的造血干细胞表现出与衰老相关的方面，并且无法在增殖应激期间保持静止。

• 发表时间: 2012-05-24
• 影响因子: 20.3
• 作者: Xiao, Nan;Jani, Kaushal;Morgan, Kelly;Okabe, Rachel;Cullen, Dana E;Jesneck, Jonathan L;Raffel, Glen D
• 通讯作者: Raffel, Glen D