Effect of somatic STAG2 mutations on clonal hematopoiesis in GATA2 associated familial myelodysplastic syndromes

体细胞STAG2突变对GATA2相关家族性骨髓增生异常综合征克隆造血的影响

基本信息

  • 批准号:
    394087903
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    Research Fellowships
  • 财政年份:
    2017
  • 资助国家:
    德国
  • 起止时间:
    2016-12-31 至 2018-12-31
  • 项目状态:
    已结题

项目摘要

GATA2 haploinsufficiency presents the most common predisposing germline defect in myeloid dysplastic syndrome (MDS) in children and is associated with a high risk of progression to acute myeloid leukemia (AML). GATA2 deficient patients often acquire additional somatic mutations in key regulators of hematopoietic stem cells which can accelerate disease progression. Mutational analysis of GATA2 deficient patients in a pilot cohort revealed a previously unknown significant enrichment of mutations in the cohesin-subunit STAG2. Biological mechanisms and effects of STAG2 mutations on disease progression in GATA2 deficient patients are currently unknown. Therefore, we will use deep targeted sequencing of bone marrow samples of patients with GATA2 deficiency syndrome in a larger cohort to identify acquired somatic mutations and to characterize clonal dynamics in serial samples. By correlating these data with clinicopathologic variables we will investigate how acquired STAG2 mutations affect the clinical phenotype. To further define the role of STAG2 mutations in hematopoietic stem cell function we will study the impact of Stag2 deficiency on hematopoietic stem cell self-renewal capacity and lineage-specific differentiation in Gata2 haploinsufficient mice. Moreover, we will determine combinatorial effects of STAG2 loss and GATA2 haploinsufficiency on global transcription, chromatin accessibility and GATA2 target gene occupancy in an isogenic myeloid leukemia cell line model to elucidate the underlying mechanisms that promote the occurrence of STAG2 mutations in GATA2 deficient patients. The investigation of pathomechanistic principles of cooperative mutations in key hematopoietic regulatory genes such as GATA2 and STAG2 and their influence on disease progression is not only essential to provide the best medical care for patients with familial MDS syndromes but also to gain a better understanding of how clonal expansion evolves in myeloid malignancies in general.
GATA 2单倍不足是儿童骨髓增生异常综合征(MDS)中最常见的易感性生殖系缺陷,并与进展为急性髓性白血病(AML)的高风险相关。GATA 2缺陷患者通常在造血干细胞的关键调节因子中获得额外的体细胞突变,这可以加速疾病进展。在试点队列中对GATA2缺陷患者的突变分析揭示了先前未知的粘着蛋白亚基STAG 2突变的显著富集。目前尚不清楚STAG 2突变对GATA 2缺陷患者疾病进展的生物学机制和影响。因此,我们将在一个更大的队列中使用GATA 2缺乏综合征患者骨髓样本的深度靶向测序,以识别获得性体细胞突变并表征系列样本中的克隆动力学。通过将这些数据与临床病理变量相关联,我们将研究获得性STAG2突变如何影响临床表型。为了进一步确定STAG2突变在造血干细胞功能中的作用,我们将研究Stag2缺陷对Gata2单倍不足小鼠造血干细胞自我更新能力和谱系特异性分化的影响。此外,我们将确定STAG 2缺失和GATA 2单倍不足对同基因骨髓白血病细胞系模型中全局转录、染色质可及性和GATA 2靶基因占用的组合影响,以阐明促进GATA 2缺陷患者中STAG 2突变发生的潜在机制。关键造血调控基因如GATA 2和STAG 2的协同突变的病理机制原理及其对疾病进展的影响的研究不仅对于为家族性MDS综合征患者提供最好的医疗护理至关重要,而且对于更好地了解一般骨髓恶性肿瘤中克隆扩增的演变方式也至关重要。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes
BCOR 和 BCORL1 突变通过断开 RING-PCGF1 酶核心与靶基因的连接来破坏白血病中 PRC1 1 的抑制功能
  • DOI:
    10.1101/2021.03.08.433705
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Schaefer E.J;Wang H.C;Meyer C.A;Cejas P;Gearhart M.D;Adelman E.R;Fares I;Apffel A;Gibson C.J;Schenone M;Murdock H.M;Wang E.S;Gondek L.P;Carroll M.P;Vedula R.S;Winer E.S;Garcia J.S;Stone R.M;Luskin M.R
  • 通讯作者:
    Luskin M.R
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Dr. Eva Johanna Schäfer其他文献

Dr. Eva Johanna Schäfer的其他文献

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