Tang Yigang, Xiao Shujun, Wang Zhengyuan, Liang Ying, Xing Yangfei, Wu Jiale, Lu Min
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Oncol. 2022 Feb 2;12:785899. doi: 10.3389/fonc.2022.785899. eCollection 2022.
Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened . Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels . Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.
对患者进行准确的预后分层可为个性化治疗提供指导。已经报道了许多急性髓系白血病（AML）的预后模型，但由于所包含的变量预测生存的能力不足且缺乏充分验证，大多数模型存在相当大的误差。在此，通过对八个独立的AML数据集进行单变量Cox回归分析，系统地鉴定了235个与AML生存密切相关的基因。对这235个基因的通路富集分析表明，IL-2/STAT5信号通路富集程度最高。通过Cox比例风险回归模型和逐步算法，我们基于与IL-2/STAT5信号通路最密切相关的生存相关基因构建了一个六基因STAT5相关特征。在训练队列（GSE37642-GPL96）中观察到良好的预后性能，并且该特征在其他七个验证队列中得到了验证。作为一个独立的预后因素，STAT5相关特征与患者年龄和ELN2017风险水平呈正相关。基于这三个预后因素的综合评分比ELN2017风险类别具有更高的预后准确性。免疫细胞浸润特征表明，B细胞适应性免疫受损、免疫抑制作用、严重感染和抗炎功能减弱往往伴随着高危患者。对内部临床样本的分析表明，AML患者的STAT5相关特征风险评分显著高于健康人。筛选出了对这些高危患者有效的五种化疗药物。在这五种药物中，已知的HDAC抑制剂MS.275选择性地抑制了STAT5磷酸化水平高的癌细胞的增殖。综上所述，数据表明STAT5相关特征是一种可靠的预后模型，可用于优化预后分层并指导AML的个性化治疗。
