Mechanisms of Leukemogenesis in Down Syndrome

唐氏综合症的白血病发生机制

• 批准号: 9043817
• 负责人: John D Crispino
• 金额: $ 30.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043817
• 关键词: Acute Lymphocytic Leukemia; Acute Megakaryocytic Leukemias; Age; Animal Model; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological Assay; Birth; Calcineurin; Cells; Child; Childhood Leukemia; Chromosomes, Human, Pair 21; Cytokine Receptors; Development; Diagnostic; Disease; Down Syndrome; ERG gene; Event; Evolution; Exhibits; Funding; GATA1 gene; Genes; Grant; Growth and Development function; Hematologic Neoplasms; Hematopoietic; Human; Human Cell Line; Human Chromosomes; Incidence; JAK2 gene; Knowledge; Lead; Malignant - descriptor; Megakaryocyte Proliferation; Megakaryocytes; Megakaryocytic Neoplasm; Megakaryocytopoieses; Methodology; Molecular Genetics; Mutation; Myeloid Leukemia; Myeloproliferative disease; NFAT Pathway; Natural History; Newborn Infant; Oncogenes; Pathway interactions; Patients; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Techniques; Testing; base; defined contribution; drug development; improved; in vivo; insight; leukemia; leukemogenesis; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; progenitor; response; screening; small hairpin RNA; transient myeloproliferative disorder

DESCRIPTION (provided by applicant): This is a competitive renewal of an NCI grant to study the contributions of trisomy 21 to hematologic malignancies. Children with DS, who have trisomy 21 in all their cells, are remarkably predisposed to leukemia, with an estimated 1 in 10 newborns exhibiting transient myeloproliferative disorder (TMD) and 1 in 500 DS children developing acute megakaryocytic leukemia (AMKL) by the age of five. In addition to myeloid leukemia, children with DS have a 20-fold increased risk of B-cell acute lymphoblastic leukemia (B-ALL). We hypothesize that overexpression of a small number of genes in the Down syndrome critical region directly lead to increased incidence of leukemia. With a greater knowledge of these genes on human chromosome 21 (Hsa21) and the specific events that occur in the evolution of these diseases, improved diagnostics and therapies can be discovered. During the previous funding period, we made many important discoveries regarding the role of trisomy 21 and GATA1 mutations in these diseases, including 1) the demonstration that mouse models of DS develop myeloproliferative disease characterized by aberrant megakaryopoiesis, 2) a detailed characterization of the role of GATA1 mutations on megakaryocyte growth and development, 3) the discovery of mutations in signaling pathways in the evolution of AMKL, 4) creation of a faithful animal model of DS-AMKL, and 6) the identification of the genes ERG and DYRK1A as the most likely leukemia oncogenes on human chromosome 21. In this renewal, we will use a combination of animal models and human patient samples to precisely determine the contributions of trisomy 21 to AMKL and ALL. Specifically, we will: 1) Determine the necessity and sufficiency of selected Hsa21 genes in human AMKL and the murine model of DS-AMKL, 2) Identify the signaling pathways that are activated in AMKL, such as NFAT which lies downstream of DYRK1A, and 3) Determine the contribution of trisomy 21 to B-ALL. In addition to providing insights into the role of trisomy 21 in DS leukemia, this research is also relevant to other leukemias with acquired trisomy 21, such as hyperdiploid ALL and to myeloproliferative neoplasms, in particular the large group of ET and PMF cases that lack JAK2 or MPL mutations.

描述（由申请人提供）：这是NCI资助的竞争性更新，用于研究21三体对血液系统恶性肿瘤的贡献。患有DS的儿童，他们的所有细胞都有21三体，非常容易患白血病，估计每10个新生儿中就有1个表现出短暂性骨髓增生性疾病（TMD），每500个DS儿童中就有1个在5岁时发展为急性巨核细胞白血病（AMKL）。除了髓系白血病，患有DS的儿童患B细胞急性淋巴细胞白血病（B-ALL）的风险增加20倍。我们假设唐氏综合征关键区域中少数基因的过度表达直接导致白血病发病率的增加。随着对人类21号染色体（Hsa 21）上的这些基因以及这些疾病演变中发生的特定事件的更多了解，可以发现改进的诊断和治疗方法。在之前的资助期间，我们就21三体和GATA 1突变在这些疾病中的作用做出了许多重要发现，包括1）证明DS小鼠模型发生以异常巨核细胞生成为特征的骨髓增生性疾病，2）详细描述GATA 1突变对巨核细胞生长和发育的作用，3）发现AMKL进化中信号通路的突变，4）建立DS-AMKL的忠实动物模型，和6）将基因ERG和DYRK 1A鉴定为人类21号染色体上最可能的白血病致癌基因。在这次更新中，我们将使用动物模型和人类患者样本的组合来精确确定21三体对AMKL和ALL的贡献。具体而言，我们将：1）确定在人AMKL和DS-AMKL的鼠模型中选择的Hsa 21基因的必要性和充分性，2）鉴定在AMKL中活化的信号传导途径，例如位于DYRK 1A下游的NFAT，和3）确定21三体对B-ALL的贡献。除了提供对21三体在DS白血病中作用的见解外，这项研究还与以下方面有关： 具有获得性21三体的其他白血病，如超二倍体ALL和骨髓增生性肿瘤，特别是缺乏JAK 2或MPL突变的大量ET和PMF病例。