Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes
Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes
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DOI：
10.1073/pnas.1516394112
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发表时间：
2015-11-17
影响因子：
11.1
通讯作者：
Wickrema, Amittha
中科院分区：
文献类型：
--
作者：
Sundaravel, Sriram;Duggan, Ryan;Wickrema, Amittha
贫血是骨髓增生异常综合征（MDS）的主要临床表现。 7 号染色体丢失或缺失在 MDS 中很常见，并导致预后不良。然而，7q 上功能相关、引起发育不良的基因的身份仍不清楚。胞质分裂专用因子 4 (DOCK4) 是一种 GTP 酶交换因子，其基因定位于通常缺失的 7q 区域。我们证明 DOCK4 在 MDS 骨髓样本中表达不足，并且表达减少与患者总体生存率降低相关。我们发现 DOCK4 水平的降低会导致红系细胞在体内和体外出现形态异常增生。我们建立了一种新型单细胞测定法来量化成红细胞中受损的 F-肌动蛋白丝网络，并证明 DOCK4 表达的减少会导致肌动蛋白丝的破坏，从而导致红细胞发育不良，从而表现出 MDS 患者样本中观察到的红细胞 (RBC) 缺陷。 -7q MDS 患者成红细胞中 DOCK4 的重新表达导致红细胞生成显着改善。 F-肌动蛋白破坏的机制表明，DOCK4 敲低可减少 ras 相关的 C3 肉毒毒素底物 1 (RAC1) GTP 酶激活，导致 MDS 样本中肌动蛋白稳定蛋白 ADDUCIN 的磷酸化增加。这些数据将 DOCK4 确定为假定的 7q 基因，其表达减少可导致红细胞发育不良。
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.