Table_2_Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy.docx

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD(-) and MRD(+)). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD(-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD(+) subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy.

目前已有多种因素被用作B细胞急性淋巴细胞白血病（B-Cell Acute Lymphoblastic Leukemia, B-ALL）患者不良临床结局的预测因子。然而，为实现更精准的治疗以获得更佳疗效并改善患者生活质量，当前仍亟需新型预后标志物。本研究旨在解析骨髓可溶性介质的特征谱，将其作为诱导治疗期间危险度分层与微小残留病（minimal residual disease, MRD）检测的潜在生物标志物。本研究共纳入47例新确诊的B细胞急性淋巴细胞白血病患者，于诱导治疗期间根据第15天的危险度分层[低危（Low Risk, LR）、低危进展为高危（Low Risk increasing to High Risk, LR→HR）及高危（High Risk, HR）]及第35天的微小残留病检测结果[MRD阴性（MRD(-)）与MRD阳性（MRD(+)）]将其划分为不同亚组。研究通过流式微球阵列技术与酶联免疫吸附试验（Enzyme-Linked Immunosorbent Assay, ELISA）对可溶性免疫介质[包括CXCL8、CCL2、CXCL9、CCL5、CXCL10、IL-1β、IL-6、肿瘤坏死因子（Tumor Necrosis Factor, TNF）、干扰素γ（Interferon-γ, IFN-γ）、IL-17A、IL-4、IL-5、IL-10及IL-2]进行了定量检测。本研究结果显示，基线水平升高的CCL5、IFN-γ及IL-2可作为低危及MRD阴性亚组患者的良好预后潜在候选标志物；而CCL2则被鉴定为与不良预后相关的稳定晚期生物标志物，该关联在高危及MRD阳性亚组的第35天样本中得以验证。此外，针对IL-17A与TNF的相关数据存在明显争议，无法明确将这两种分子界定为阳性或阴性预后生物标志物。本研究结果为新型预后指标的筛选提供了参考，并揭示了骨髓可溶性介质在B细胞急性淋巴细胞白血病患者诱导治疗期间的预后评估与随访监测中的应用潜力。