通过风险适应性的初级治疗方法完全消除B-细胞性急性淋巴细胞白血病（B-ALL）仍然是一个临床的重要目标，但在三分之一的患者中失败。最近的证据表明，具有干细胞特征的B-ALL细胞亚群参与了疾病持续存在。我们假设，作为造血和白血病干细胞的核心调节因子，microRNA-126可能会解决B-ALL的肿瘤内异质性，并揭示耐药亚群。我们利用了带有miR-126报告基因的B-ALL细胞转导的患者源异种移植模型（PDX模型），以便前瞻性分离miR-126(high)细胞并进行其功能和转录特征分析。在9个PDX模型的8个模型中鉴定出离散的miR-126(high)亚群，这些亚群通常具有MIR126位点去甲基化，并显示出增加的再集落能力、体内化疗耐药性和休眠、炎症和应激反应通路激活的特征。通过单细胞RNA测序，我们确定了表达miR-126(high)的细胞在成人和儿童B-ALL的诊断样本中作为不同的疾病亚群存在。在接受标准化治疗的几个儿童和成人B-ALL队列中测试了miR-126的表达和位点去甲基化。诊断时的高microRNA-126水平和位点去甲基化与诱导化疗的亚优反应相关（MRD > 0.05%在第33天或MRD+在第78天）。©2023.作者授权Springer Nature Limited独家使用。

Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intratumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus demethylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single-cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus demethylation at diagnosis associate with suboptimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78).© 2023. The Author(s), under exclusive licence to Springer Nature Limited.