S100A16 suppresses the growth and survival of leukaemia cellsand correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia
S100A16 suppresses the growth and survival of leukaemia cellsand correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia
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S100A16 抑制白血病细胞的生长和存活，并与费城染色体阴性 B 细胞急性淋巴细胞白血病成人患者的复发和无复发存活相关
DOI：
10.1111/bjh.15878
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发表时间：
2019
影响因子：
6.5
通讯作者：
Liu Kai-Yan
中科院分区：
文献类型：
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作者：
Zhang Jing;Lu Wen-Yi;Zhang Jia-Min;Lu Run-Qing;Wu Li-Xin;Qin Ya-Zhen;Liu Yan-Rong;Lai Yue-Yun;Jiang Hao;Jiang Qian;Jiang Bin;Xu Lan-Ping;Zhang Xiao-Hui;Huang Xiao-Jun;Ruan Guo-Rui;Liu Kai-Yan
费城染色体(Ph)阴性的B细胞急性淋巴细胞性白血病(ALL)风险分层的改进可能有助于识别可能复发的患者。异常S100钙结合蛋白A16(S100A16)与多种癌症有关，但其功能尚不清楚。我们发现130例新诊断为Ph阴性的成人B细胞的S100A16转录水平均高于33例健康对照。在获得首次完全缓解的115例患者中，S100A16基因转录水平高的患者3年累计复发率较低(CIR：34%[21，47%]对40%[48，72%]；P=0.012)，三年无复发生存率较高(RFS：65%[53，78%]对35%[23，46%]；P=0.012)。在多因素分析中，S100A16转录本水平低与较高的CIR(危险比[HR]=10.3·74[1·01-13·82]；P=0.048)和较差的RFS(HR=9.78[1.91，17·84]；P<；0·001)独立相关。功能分析表明，S100A16基因的敲除促进了细胞的增殖和抗凋亡，降低了对化疗的敏感性，而S100A16的过度表达则显示出相反的趋势，尤其是在异种移植小鼠模型中。Western blotting分析显示，在S100A16基因敲除和S100A16过表达的B细胞ALL细胞系中，PI3K/AKT和ERK1/2分别上调。抑制实验表明这两条信号通路参与了S100A16介导的B细胞ALL细胞系的增殖和存活效应。试验注册：注册于中国临床试验注册文献[CHICCTR-OCH-10000940]；http://www.chictr.org.cn.
Refinement of risk stratification in Philadelphia chromosome (Ph)‐negative B‐cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. AbnormalS100 calcium binding proteinA16 (S100A16) has been implicated in various cancers, but its function remains unclear. We foundS100A16transcript levels were higher in 130 adults with newly‐diagnosed Ph‐negative B‐cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with highS100A16transcript levels displayed a lower 3‐year cumulative incidence of relapse (CIR; 34% [21, 47%] vs. 40% [48, 72%];P=0·012) and higher 3‐year relapse‐free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%];P=0·012), especially when receiving chemotherapy only. In multivariate analysis a lowS100A16transcript level was independently‐associated with a higher CIR (Hazard ratio [HR] = 3·74 [1·01–13·82];P=0·048) and inferior RFS (HR = 5·78 [1·91, 17·84];P<0·001). Function analysis indicated that knockdown ofS100A16promoted proliferation and anti‐apoptosis and reduced chemosensitivity.S100A16over‐expression revealed an opposite trend, especially in a xeno‐transplant mouse model. Western blotting analysis showed upregulation of PI3K/AKT and ERK1/2 inS100A16‐knockdown andS100A16‐overexpression B‐cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in theS100A16‐mediated proliferation and survival effects in B‐cell ALL cell lines.Trial Registration:Registered in the Chinese Clinical Trial Registry [ChiCTR‐OCH‐10000940]; http://www.chictr.org.cn.