Wang Jiali, Qian Bo, Yu Xiaowen, Zhang Yidan, Zhou Chunlei, Yang Tingting, Xia Le, Zhang Gang, Zhang Yi-Xuan, Wang Yaping, Fang Yongjun
Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
Clin Transl Med. 2025 Jul;15(7):e70380. doi: 10.1002/ctm2.70380.
The clinical guideline classifies T-LBL and T-ALL jointly, differentiating them merely by the bone marrow blast cell proportion. However, their distinct clinical manifestations, genetic profiles, and specific pathogenic requirements have prompted us to reevaluate the differences between them.
We established the NCH-TALL-LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T-LBL samples and implemented single-cell RNA sequencing and single-cell T-cell receptor sequencing. Combining the single-cell RNA sequencing data of T-ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T-LBL are predominantly in the DN- and DP-stage blocking modes (DP cells dominate). This block mode in T-LBL generates signals that drive the development of an immunosuppressive microenvironment and the mediastinum preference. Additionally, E2F2, an active transcription factor in the DP and DN stages, upregulates the expression of UHRF1, resulting in hypermethylation of tumor suppressor genes. Findings from in vivo and in vitro research clearly show that demethylation therapy targeting this mechanism effectively inhibits tumor proliferation in T-LBL.
From the perspective of differentiation blockage, T-LBL and T-ALL represent different stages of the same disease, and the stage block bias of T-cell contributes to their heterogeneity.
Malignant T cells in T-LBL are primarily blocked in the DN and DP stages, which contributes to the immunosuppressive TME and mediastinum preference of T-LBL. The active transcription factor E2F2 in the DP and DN stages upregulates UHRF1 expression, leading to the hypermethylation of tumor suppressor genes in T-LBL. Demethylation therapy targeting the hypermethylation of tumor suppressor genes mediated by UHRF1 effectively inhibits tumor proliferation in T-LBL.
临床指南将T淋巴母细胞淋巴瘤（T-LBL）和T淋巴细胞白血病（T-ALL）合并分类，仅通过骨髓原始细胞比例对它们进行区分。然而，它们不同的临床表现、基因特征和特定的致病条件促使我们重新评估它们之间的差异。
我们建立了NCH-TALL-LBL队列，其中包括来自我们中心的流式细胞术数据和体细胞突变数据。此外，我们收集了T-LBL样本并进行了单细胞RNA测序和单细胞T细胞受体测序。结合T-ALL的单细胞RNA测序数据、表达阵列数据和流式细胞术数据，我们发现T-LBL中的恶性T细胞主要处于双阴性（DN）和双阳性（DP）阶段阻滞模式（DP细胞占主导）。T-LBL中的这种阻滞模式产生驱动免疫抑制微环境发展和纵隔偏好的信号。此外，DP和DN阶段的活性转录因子E2F2上调泛素样含PHD和RING结构域蛋白1（UHRF1）的表达，导致肿瘤抑制基因的高甲基化。体内和体外研究结果清楚地表明，针对这一机制的去甲基化治疗可有效抑制T-LBL中的肿瘤增殖。
从分化阻滞的角度来看，T-LBL和T-ALL代表同一疾病的不同阶段，T细胞的阶段阻滞偏向导致了它们的异质性。
T-LBL中的恶性T细胞主要阻滞在DN和DP阶段，这导致了T-LBL的免疫抑制性肿瘤微环境（TME）和纵隔偏好。DP和DN阶段的活性转录因子E2F2上调UHRF1表达，导致T-LBL中肿瘤抑制基因的高甲基化。针对由UHRF1介导的肿瘤抑制基因高甲基化的去甲基化治疗可有效抑制T-LBL中的肿瘤增殖。
