Song Yang, Liu Ting, Hao Qishan, Fang Qiuyun, Gong Xiaoyuan, Li Yan, Tian Zheng, Wei Hui, Wang Min, Wang Jianxiang, Cheng Tao, Mi Yingchang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tianjin Institutes of Health Science, Tianjin, China.
Mol Oncol. 2025 May 19. doi: 10.1002/1878-0261.70053.
B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease with a challenging prognosis, particularly in adult patients. We enrolled 88 adult B-ALL patients with transcriptomic and mutation profiles for classification system identification, and a comprehensive system for B-ALL patients (COMBAT) was developed. COMBAT stratified patients into three cohorts: (1) COMBAT1, characterized by high stem/myeloid antigen expression, low immune infiltration, high infiltration of endothelial cells, and hypo-CIMP (CpG island methylator phenotype); (2) COMBAT2, defined as an inflamed subtype with immune exhaustion, moderate myeloid antigen expression, and hypo-CIMP; and (3) COMBAT3, marked by proliferative profiles with MYC pathway activation and hypomethylation at enhancer regions in patients characterized by CIMP. The molecular features of the three COMBATs were verified in two external cohorts, the GSE34861 (N = 194) and GSE66005 (N = 109) datasets. In univariate analysis, only COMBAT classification presented significance for OS, and patients of COMBAT3 presented significantly superior survival than COMBAT1/2 in Ph-negative ALL. Ph-negative ALL patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the COMBAT3 group showed better overall survival (OS) than those in the COMBAT1-2 groups (estimated 3-year OS: 100% vs. 65.6%, P = 0.034), suggesting a prognostic benefit of this subtype. In summary, the COMBAT system redefines the characteristics of adult B-ALL subtypes and guides the selection of allo-HSCT for Ph-negative patients.
B 细胞急性淋巴细胞白血病（B-ALL）是一种高度异质性疾病，预后具有挑战性，尤其是在成年患者中。我们招募了 88 名成年 B-ALL 患者，获取其转录组和突变谱以进行分类系统识别，并开发了一个针对 B-ALL 患者的综合系统（COMBAT）。COMBAT 将患者分为三个队列：（1）COMBAT1，其特征为高干细胞/髓系抗原表达、低免疫浸润、高内皮细胞浸润和低 CIMP（CpG 岛甲基化表型）；（2）COMBAT2，定义为具有免疫耗竭、中等髓系抗原表达和低 CIMP 的炎症亚型；（3）COMBAT3，其特征为具有 MYC 通路激活和 CIMP 特征患者增强子区域低甲基化的增殖谱。在两个外部队列 GSE34861（N = 194）和 GSE66005（N = 109）数据集中验证了这三个 COMBAT 的分子特征。在单变量分析中，只有 COMBAT 分类对总生存期具有显著意义，并且在 Ph 阴性 ALL 中，COMBAT3 患者的生存期明显优于 COMBAT1/2。COMBAT3 组中接受异基因造血干细胞移植（allo-HSCT）的 Ph 阴性 ALL 患者的总生存期（OS）优于 COMBAT1-2 组（估计 3 年 OS：100% 对 65.6%，P = 0.034），表明该亚型具有预后优势。总之，COMBAT 系统重新定义了成年 B-ALL 亚型的特征，并指导 Ph 阴性患者 allo-HSCT 的选择。
