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: 7176783
• 负责人: Glen D Raffel
• 金额: $ 13.44万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176783
• 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; Protein Overexpression; Proteins; Reagent; Regulation; Role; Therapeutic Intervention; in vivo; insight; leukemia; leukemogenesis; mouse model; novel; 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）：大多数婴儿急性巨核细胞白血病（AMKL）在非下降综合征儿童中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（又称RBM15）和MAL（又称MKL1/MRTF-A/BSAC），并导致嵌合蛋白的表达。融合中的同源结构基序已在已知参与分化，增殖和白血病发生的蛋白质中鉴定出来。为了阐明OTT-MAL融合蛋白诱导的病理生理学，已经使用敲入方法从OTT基因座表达OTT-MAL产生了小鼠。通过从内源OTT启动子表达融合蛋白，应复制在人白血病中发现的OTT-MAL的化学计量和表达模式。不断发展的数据表明，基因剂量和调节的细微差异对白血病发生和正常的巨毛毛虫具有关键影响。 识别OTT-MAL可能诱导白血病发生的途径将需要对成分基因，OTT和MAL的造血作用更全面地理解。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。 OTT-MAL在T（1; 22）AMKL中的作用将使用常规模型进行研究以解决以下问题： 特定目标1。小鼠OTT-MAL表达的后果是什么？ 具体目标2。OTT的体内生理作用是什么？OTT-MAL Fusion蛋白利用了内源性OTT的哪些途径？ 特定目标3。MAL功能在正常生理学和OTT-MAL介导的失调中具有什么作用？ T（1; 22）AMKL的鼠模型的建立和分析将为研究AMKL，潜在的治疗干预措施和对巨核细胞开发的基本见解提供新的机会。