Mechanisms of leukemogenesis in Down syndrome

唐氏综合症的白血病发生机制

• 批准号: 10307029
• 负责人: John D Crispino
• 金额: $ 12.56万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-11 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307029
• 关键词: Mechanisms; leukemogenesis; Down; syndrome

PROJECT SUMMARY This is a competitive renewal of our NCI funded grant to study the contributions of trisomy 21 to hematologic malignancies. Children with Down syndrome (DS), who have trisomy 21 in 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 that trisomy 21 directly and functionally contributes to the malignant transformation of hematopoietic cells. In particular, we believe that increased expression of the kinase DYRK1A and chromosome assembly factor CHAF1B directly contribute to the increased incidence of leukemia in this population. 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. We: 1) Identified several candidate megakaryocytic leukemia promoting genes in the Down syndrome critical region of chromosome 21, including DYRK1A, CHAF1B and ERG; 2) Showed that the Ts1Rhr animal model of DS, which is trisomic for 31 genes that parallel the human Down syndrome critical region, faithfully mimics DS-AMKL when GATA1 and MPL mutations, two alterations that are associated with DS-AMKL, are introduced; 3) Demonstrated that overexpression of ERG and the presence of the leukemic GATA1 isoform GATA1s cooperate with AKT in aberrant megakaryopoiesis; 4) Revealed that Dyrk1a is essential for both B and T cell development through its regulation of cyclin D3 stability and that inhibition of Dyrk1a leads to a lymphoid, but not myeloid, deficiency, 5) Discovered that evolution of trisomy 21 to transient leukemia and then AMKL is associated with progressive epigenetic changes; and 6) Showed, in collaboration with David Weinstock, that trisomy of HMGN1 promotes B-ALL. In this renewal, we will focus on two candidate leukemia promoting genes on chromosome 21, the kinase DYRK1A and the nucleosome assembly factor CHAF1B. Our specific aims are to: 1) Determine the role of DYRK1A and its substrate STAT3 in leukemia in children with DS, and 2) Define the contributions of CHAF1B to normal and malignant hematopoiesis. In addition to providing insights into the role of trisomy 21 in DS leukemia, this research is also relevant to general B-cell ALL and other leukemias with acquired trisomy 21, such as hyperdiploid ALL.

项目摘要 这是我们的NCI资助赠款的竞争性更新，用于研究21三体对血液学的贡献。 恶性肿瘤。患有唐氏综合症（DS）的儿童，他们的细胞中有21三体， 易患白血病，估计每10个新生儿中就有1个表现出一过性骨髓增生性疾病 (TMD)在5岁时，每500名DS儿童中就有1名发生急性巨核细胞白血病（AMKL）。在 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的风险增加20倍。 白血病（B-ALL）。我们假设21三体直接和功能性地促进了 造血细胞的恶性转化。特别是，我们认为， 激酶DYRK 1A和染色体组装因子CHAF 1B直接导致了 白血病在这一人群中的发病率。随着对人类染色体上这些基因的更多了解， 21（Hsa 21）和这些疾病演变过程中发生的特定事件，改进的诊断和 可以发现治疗方法。在上一个资助期内，我们取得了许多重要发现 关于21三体和GATA 1突变在这些疾病中的作用。我们：1）确定了几个候选人 21号染色体唐氏综合征关键区域中的巨核细胞白血病促进基因，包括 结果表明：1）DS动物模型Ts 1 Rhr为31个基因的三体， 与人类唐氏综合征关键区域平行，当GATA 1和MPL 引入突变，即与DS-AMKL相关的两种改变; 3）证明， ERG的过表达和白血病GATA 1亚型GATA 1的存在与AKT协同作用， 异常巨核细胞生成; 4）揭示Dyrk 1a通过其对B和T细胞发育至关重要 细胞周期蛋白D3稳定性的调节和Dyrk 1a的抑制导致淋巴样而非髓样缺陷，5） 发现21三体突变为短暂性白血病，然后AMKL与进行性白血病相关， 表观遗传变化; 6）与大卫温斯托克合作显示，HMGN 1的三体性促进了 B-ALL。在这次更新中，我们将重点关注21号染色体上的两个候选白血病促进基因， 激酶DYRK 1A和核小体组装因子CHAF 1B。我们的具体目标是：1）确定角色 DYRK 1A及其底物STAT 3在DS儿童白血病中的作用，以及2）确定 CHAF 1B对正常和恶性造血的影响。除了深入了解21三体在 DS白血病，这项研究也与一般B细胞ALL和其他获得性21三体白血病有关， 例如超二倍体ALL。