Progressive genomic instability in the Nup98-HoxD13 model of MDS correlates with loss of the PIG-A gene product.
Progressive genomic instability in the Nup98-HoxD13 model of MDS correlates with loss of the PIG-A gene product.
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DOI：
10.1016/j.neo.2014.07.004
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发表时间：
2014-08
期刊：
影响因子：
4.8
通讯作者：
May, W. Stratford
中科院分区：
文献类型：
--
作者：
Byrne, Michael;Bennett, Richard L.;Cheng, Xiaodong;May, W. Stratford
Nup 98-HoxD 13（NHD 13）融合基因在治疗相关的骨髓增生异常综合征（MDS）患者中鉴定。当在造血细胞中转基因表达时，小鼠忠实地再现了人类疾病，从外周血（PB）血细胞减少和骨髓（BM）母细胞增加到急性白血病的连续进展。发育不良造血干/祖细胞（HSPC）中的基因组不稳定性驱动MDS向急性白血病的演变是公认的。研究结果表明，与野生型对照相比，NHD 13小鼠的网织红细胞、骨髓和淋巴PB细胞显示出与年龄相关的糖基磷脂酰肌醇连接的表面蛋白损失增加。这些数据与通过γ-H2 AX活性测量的DNA损伤反应的进行性增加、随着疾病进展而积累BM母细胞以及最终发展为急性白血病相关。这些发现清楚地证明了进行性基因组不稳定性的状态，其增加了疾病后期“二次命中”或互补突变的可能性以触发急性白血病的发展，并强调了NUP 98-HoxD 13转基因如何诱导MDS进展为急性白血病的机制性质。此外，这些数据支持使用PIG-A检测试剂作为MDS HSPC中发生的基因组不稳定性的有效实时替代标记物。关键点PIG-A检测是一种灵敏的非致死性方法，可用于MDS小鼠模型中基因组不稳定性的系列评估。
The Nup98-HoxD13 (NHD13) fusion gene was identified in a patient with therapy-related myelodysplastic syndrome (MDS). When transgenically expressed in hematopoietic cells, mice faithfully recapitulate human disease with serial progression from peripheral blood (PB) cytopenias and increased bone marrow (BM) blasts to acute leukemia. It is well accepted that genomic instability in dysplastic hematopoietic stem/progenitor cells (HSPC) drives the evolution of MDS to acute leukemia. Findings here demonstrate that reticulocytes, myeloid and lymphoid PB cells of NHD13 mice, display an increase in the age-associated loss of glycosylphosphatidylinositol-linked surface proteins versus wild type controls. These data correlate with a progressive increase in the DNA damage response as measured by γ-H2AX activity, accumulating BM blasts as the disease progresses and finally development of acute leukemia. These findings clearly demonstrate a state of progressive genomic instability that increases the likelihood of a “second hit” or complimentary mutation later in the disease to trigger development of acute leukemia and underscores the mechanistic nature of how the NUP98-HoxD13 transgene induces progression of MDS to acute leukemia. Additionally, these data support the use of the PIG-A assay as an efficient, real-time surrogate marker of the genomic instability that occurs in the MDS HSPCs. Key Point The PIG-A assay is a sensitive, nonlethal method for the serial assessment of genomic instability in mouse models of MDS.
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影响因子：
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DOI：
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发表时间：
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期刊：
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