成人急性髓系白血病中Roundabout 4（robo4）的临床及预后意义
Clinical and prognostic implications of Roundabout 4 (robo4) in adult patients with acute myeloid leukemia.
作者信息
Chen Yin-Kai, Hou Hsin-An, Tang Jih-Luh, Jhuang Jie-Yang, Lai Yan-Jun, Lee Ming-Cheng, Kuo Yuan-Yeh, Chou Wen-Chien, Liu Chieh-Yu, Lin Chung-Wu, Chuang Shih-Sung, Chen Chien-Yuan, Tseng Mei-Hsuan, Huang Chi-Fei, Chiang Ying-Chieh, Lee Fen-Yu, Liu Ming-Chih, Liu Chia-Wen, Yao Ming, Huang Shang-Yi, Ko Bor-Sheng, Hsu Szu-Chun, Wu Shang-Ju, Tsay Woei, Chen Yao-Chang, Tien Hwei-Fang
机构信息
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin branch, Yun-Lin, Taiwan.
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
出版信息
PLoS One. 2015 Mar 20;10(3):e0119831. doi: 10.1371/journal.pone.0119831. eCollection 2015.
BACKGROUND
Robo4 is involved in hematopoietic stem/progenitor cell homeostasis and essential for tumor angiogenesis. Expression of Robo4 was recently found in solid tumors and leukemia stem cells. However, the clinical implications of Robo4 expression in patients with acute myeloid leukemia (AML) remain unclear.
METHODS
We investigated the clinical and prognostic relevance of mRNA expression of Robo4 in bone marrow (BM) mononuclear cells from 218 adult patients with de novo AML. We also performed immunohistochemical staining to assess the Robo4 protein expression in the BM biopsy specimens from 30 selected AML patients in the cohort.
RESULTS
Higher Robo4 expression was closely associated with lower white blood cell counts, expression of HLA-DR, CD13, CD34 and CD56 on leukemia cells, t(8;21) and ASXL1 mutation, but negatively correlated with t(15;17) and CEBPA mutation. Compared to patients with lower Robo4 expression, those with higher expression had significantly shorter disease-free survival (DFS) and overall survival (OS). This result was confirmed in an independent validation cohort. Furthermore, multivariate analyses showed that higher Robo4 expression was an independent poor prognostic factor for DFS and OS in total cohort and patients with intermediate-risk cytogenetics, irrespective of age, WBC count, karyotype, and mutation status of NPM1/FLT3-ITD, and CEBPA.
CONCLUSIONS
BM Robo4 expression can serve as a new biomarker to predict clinical outcomes in AML patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression.
背景
Robo4参与造血干/祖细胞稳态维持，对肿瘤血管生成至关重要。最近在实体瘤和白血病干细胞中发现了Robo4的表达。然而，Robo4表达在急性髓系白血病（AML）患者中的临床意义仍不清楚。
方法
我们研究了218例初发AML成年患者骨髓（BM）单个核细胞中Robo4 mRNA表达的临床及预后相关性。我们还进行了免疫组化染色，以评估队列中30例选定AML患者BM活检标本中Robo4蛋白的表达。
结果
较高的Robo4表达与较低的白细胞计数、白血病细胞上HLA-DR、CD13、CD34和CD56的表达、t(8;21)和ASXL1突变密切相关，但与t(15;17)和CEBPA突变呈负相关。与Robo4表达较低的患者相比，表达较高的患者无病生存期（DFS）和总生存期（OS）明显较短。这一结果在独立验证队列中得到证实。此外，多变量分析表明，较高的Robo4表达是整个队列以及具有中等风险细胞遗传学患者DFS和OS的独立不良预后因素，与年龄、白细胞计数、核型以及NPM1/FLT3-ITD和CEBPA的突变状态无关。
结论
BM中Robo4表达可作为预测AML患者临床结局的新生物标志物，Robo4可能是Robo4表达较高患者的潜在治疗靶点。
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