Mechanisms of Leukemogenesis in Down Syndrome

唐氏综合症的白血病发生机制

基本信息

  • 批准号:
    9913474
  • 负责人:
  • 金额:
    $ 22.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-05-01 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

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.
项目总结 这是我们NCI资助的研究21三体对血液学的贡献的竞争性更新。 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,显著地 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生性疾病 每500名DS儿童中就有1名在5岁前患上急性巨核细胞白血病(AMKL)。在……里面 除髓系白血病外,患有DS的儿童患B细胞急性淋巴母细胞白血病的风险增加20倍 白血病(B-ALL)。我们假设21三体在功能上直接影响了 造血细胞的恶性转化。特别是,我们认为,增加的表达 激酶DYRK1A和染色体组装因子CHAF1B直接导致了 白血病在这一人群中的发病率。对人类染色体上的这些基因有更多的了解 21(HSA21)和在这些疾病的演变中发生的具体事件,改进的诊断和 治疗方法是可以发现的。在上一次融资期间,我们取得了许多重要发现。 关于21三体和GATA1突变在这些疾病中的作用。我们:1)确定了几位候选人 21号染色体唐氏综合征临界区的巨核细胞白血病促进基因,包括 DYRK1A、CHAF1B和ERG;2)显示DYRK1A、CHAF1B和ERG是由31个基因三体组成的DS动物模型 与人类唐氏综合症临界区平行,忠实地模拟了当GATA1和MPL 突变,两种与DS-AMKL相关的改变;3)证明 ERG的过度表达和白血病GATA1亚型GATA1与AKT的协同作用 异常的巨核细胞生成;4)揭示了Dyrk1a对B和T细胞的发育是必不可少的 调节细胞周期蛋白D3的稳定性和抑制Dyrk1a导致淋巴系而不是髓系缺乏症,5) 发现21三体演变为一过性白血病和AMKL与进展性白血病相关 表观遗传学变化;以及6)与大卫·温斯托克合作表明,HMGN1的三体促进 B-全部。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,即 激酶DYRK1A和核小体组装因子CHAF1B。我们的具体目标是:1)确定角色 DYRK1A及其底物STAT3在DS儿童白血病中的表达,以及2)确定DYRK1A及其底物STAT3的贡献 CHAF1B对正常和恶性造血的影响。除了提供对21三体在 DS白血病,这项研究也与普通B细胞ALL和其他带有获得性21三体的白血病有关, 如超二倍体ALL等。

项目成果

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John D Crispino其他文献

John D Crispino的其他文献

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{{ truncateString('John D Crispino', 18)}}的其他基金

Identifying the pathways that drive progression of the MPNs to AML
确定推动 MPN 进展为 AML 的途径
  • 批准号:
    10307030
  • 财政年份:
    2021
  • 资助金额:
    $ 22.83万
  • 项目类别:
Identifying the mechanisms of leukemia progression
确定白血病进展的机制
  • 批准号:
    10677759
  • 财政年份:
    2021
  • 资助金额:
    $ 22.83万
  • 项目类别:
Aberrant megakaryopoiesis in the myleoproliferative neoplasms
骨髓增生性肿瘤中异常的巨核细胞生成
  • 批准号:
    10307918
  • 财政年份:
    2021
  • 资助金额:
    $ 22.83万
  • 项目类别:
Identifying the mechanisms of leukemia progression
确定白血病进展的机制
  • 批准号:
    10298553
  • 财政年份:
    2021
  • 资助金额:
    $ 22.83万
  • 项目类别:
Mechanisms of leukemogenesis in Down syndrome
唐氏综合症的白血病发生机制
  • 批准号:
    10307029
  • 财政年份:
    2021
  • 资助金额:
    $ 22.83万
  • 项目类别:
GATA1 Mutation in Defective Erythropoiesis
红细胞生成缺陷中的 GATA1 突变
  • 批准号:
    8651635
  • 财政年份:
    2013
  • 资助金额:
    $ 22.83万
  • 项目类别:
Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms
骨髓增生性肿瘤中异常的巨核细胞生成
  • 批准号:
    8707548
  • 财政年份:
    2013
  • 资助金额:
    $ 22.83万
  • 项目类别:
GATA1 Mutation in Defective Erythropoiesis
红细胞生成缺陷中的 GATA1 突变
  • 批准号:
    9115144
  • 财政年份:
    2013
  • 资助金额:
    $ 22.83万
  • 项目类别:
GATA1 Mutation in Defective Erythropoiesis
红细胞生成缺陷中的 GATA1 突变
  • 批准号:
    8737256
  • 财政年份:
    2013
  • 资助金额:
    $ 22.83万
  • 项目类别:
Aberrant megakaryopoiesis in the myeloproliferative neoplasms.
骨髓增生性肿瘤中异常的巨核细胞生成。
  • 批准号:
    9922938
  • 财政年份:
    2013
  • 资助金额:
    $ 22.83万
  • 项目类别:
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