Mechanisms of Leukemogenesis in Down Syndrome

描述（由申请人提供）：患有唐氏综合症的儿童患某种形式白血病的风险增加10-20倍，患急性巨核母细胞白血病（DS-AMKL）的风险增加500倍。此外，患有退行性椎体滑移的婴儿通常会受到一种相关的髓系疾病的影响，这种疾病被称为短暂性骨髓增生性疾病（TMD）。我们最近证明造血转录因子GATA1在几乎所有的TMD和DS-AMKL病例中都发生突变。在每种情况下，突变都导致全长GATA-1的表达缺失，但允许翻译一个缩短的同工异构体GATA-1，它保留了DMA结合锌指，但缺少n端反激活结构域。我们发现GATA-1可以挽救GATA-1缺陷巨核细胞的终末分化，但不能限制其超增殖表型：这些观察结果使我们假设由于该短同种异构体的表达而导致的基因调控失衡参与了TMD和DS-AMKL的发病机制。关于21三体在AMKL中的作用，我们发现最广泛使用的DS小鼠模型Ts65Dn小鼠发展为骨髓增生性疾病（MPD），其特征是血小板增多、骨髓纤维化和巨核细胞谱系的显着扩增。这表明21三体直接导致异常巨核生成，并为我们提供了一个识别相关特定基因的平台。在这里，我们提出定义GATA1突变和21三体在AMKL中的作用。具体来说，我们计划：1)在小鼠DS模型中表征骨髓增生性疾病，2)鉴定导致该疾病的人类21号染色体基因的小鼠同源基因（以及延伸到DS-AMKL），以及3)使用小鼠模型评估GATA1, 21三体和AMKL中JAK激酶突变形式之间的遗传相互作用。我们的研究结果将增加我们对GATA1突变如何促进DS中白血病的发生或进展的理解，也可能导致人类21号染色体上新的白血病疾病基因的鉴定。此外，由于许多白血病，如超二倍体ALL，在其进化过程中获得额外的21号染色体拷贝；我们的工作可能与其他更常见的造血恶性肿瘤有关。摘要：这项研究将为唐氏综合症儿童白血病的病因提供见解，并可能导致改进的治疗和诊断。此外，该研究还可能对其他人类血液疾病（如骨髓增生性疾病）的病因学产生影响。

DESCRIPTION (provided by applicant): Children with Down syndrome face a 10-20 fold increased risk of developing some form of leukemia and a 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). Furthermore, infants with DS are commonly and uniquely affected by a related myeloid disease, named transient myeloproliferative disorder (TMD). We recently demonstrated that the hematopoietic transcription factor GATA1 is mutated in nearly all cases of both TMD and DS-AMKL. In every case, the mutation results in loss of expression of full-length GATA-1, but allows for translation of a shortened isoform, GATA-1s, which retains both DMA binding zinc fingers, but is missing the N-terminal transactivation domain. We have found that GATA-1s can rescue the terminal differentiation of GATA-1 deficient megakaryocytes, but it fails to restrict their hyperproliferative phenotype: these observations lead us to hypothesize that an imbalance of gene regulation due to the expression of this short isoform contributes to the pathogenesis of TMD and DS-AMKL. With respect to the role of trisomy 21 in AMKL, we discovered that the most widely used mouse model of DS, Ts65Dn mice, develop a myeloproliferative disorder (MPD) characterized by thrombocytosis, myelofibrosis and a marked expansion in the megakaryocyte lineage. This suggests that trisomy 21 directly contributes to aberrant megakaryopoiesis and provides us with a platform for identifying the specific genes involved. Here we propose to define the role of GATA1 mutations and trisomy 21 in AMKL. Specifically we plan to: 1) characterize the myeloproliferative disease in mouse models of DS, 2) identify the mouse orthologs of human chromosome 21 genes that contribute to this disease (and, by extension, to DS-AMKL), and 3) assess the genetic interaction between GATA1, trisomy 21 and mutant forms of JAK kinases in AMKL, using mouse models. The results of our research will increase our understanding of how GATA1 mutations contribute to the initiation or progression of leukemia in DS and may also lead the identification of novel leukemia disease genes on human chromosome 21. In addition, since much leukemia, such as hyper- diploid ALL, acquire additional copies of chromosome 21 during their evolution; our work will likely have relevance to other more common forms of hematopoietic malignancies. Lay Summary: This research will provide insight to the cause of leukemia in children with Down syndrome and may lead to improved therapies and diagnostics. Furthermore, the research may also have impact on the etiology of other human blood diseases, such as myeloproliferative disorders.