Mechanisms of Leukemogenesis in Down Syndrome

描述(由申请人提供)：这是一项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。所有细胞都有21三体的DS儿童极易患白血病，估计每10名新生儿中就有1人表现出一过性骨髓增殖性疾病(TMD)，每500名DS儿童中就有1人在5岁前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，唐氏综合征临界区少量基因的过度表达直接导致白血病发病率的增加。通过更多地了解人类21号染色体上的这些基因(Hsa21)以及这些疾病进化过程中发生的具体事件，可以发现改进的诊断和治疗方法。在上一个资助期内，我们在21三体和GATA1突变在这些疾病中的作用方面取得了许多重要发现，包括1)证明了DS的小鼠模型会发展以异常巨核细胞生成为特征的骨髓增殖性疾病，2)详细描述了GATA1突变对巨核细胞生长和发育的作用，3)发现了AMKL进化中的信号通路突变，4)建立了忠实的DS-AMKL动物模型，6)确定ERG和DYRK1A基因是人类21号染色体上最有可能的白血病癌基因。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。具体来说，我们将：1)确定在人AMKL和DS-AMKL小鼠模型中选择Hsa21基因的必要性和充分性；2)确定在AMKL中激活的信号通路，如位于DYRK1A下游的NFAT；3)确定21三体对B-ALL的贡献。除了为21三体在DS白血病中的作用提供见解外，这项研究还与 其他具有获得性21三体的白血病，如超二倍体ALL和骨髓增殖性肿瘤，特别是大量缺乏JAK2或MPL突变的ET和PMF病例。

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.