T细胞受体结构和克隆追踪揭示外周T细胞淋巴瘤的转化轨迹

T-cell receptor architecture and clonal tiding provide insight into the transformation trajectory of peripheral T-cell lymphomas

HAEMATOLOGICA

影响因子:7.9

分区:医学1区 Top / 血液学2区

发表日期:2025 Feb 01

作者: Edith Willscher, Christoph Schultheiß, Lisa Paschold, Franziska Lea Schümann, Paul Schmidt-Barbo, Benjamin Thiele, Marcus Bauer, Claudia Wickenhauser, Thomas Weber, Mascha Binder

DOI: 10.3324/haematol.2024.285395

摘要

虽然T细胞淋巴瘤被归类为成熟肿瘤，但新证据表明恶性转化可能发生在T细胞成熟的早期。本研究在广泛的T细胞淋巴瘤中确定了克隆结构。多维度分析显示，这些淋巴瘤中的许多实际上起源于未成熟的淋巴T细胞前体，位于V(D)J重排之前的发育阶段，并经历分支演化。在单细胞分辨率下，我们观察到在选择性治疗压力下存在显著的克隆追踪。T细胞受体二代测序显示，TRBV20-1基因片段的使用具有高度偏向性，代表每位患者多重抗原受体重排的一部分。TRBV20-1在所有主要T细胞淋巴瘤亚型中均占优势，提示这一特定V基因（无论其互补决定区3的构型如何）可能是驱动恶性转化的关键因素。综上所述，我们的数据显示，T细胞淋巴瘤起源于未成熟的淋巴前体细胞，并表现出明显的肿瘤内异质性，这可能为这些难治性癌症的复发和耐药提供基础。

Abstract

While T-cell lymphomas are classified as mature neoplasms, emerging evidence indicates that malignant transformation may occur at an earlier stage of T-cell maturation. In this study, we determined clonal architecture in a broad range of T-cell lymphomas. Our multidimensional profiling indicates that many of these lymphomas do in fact emerge from an immature lymphoid T-cell precursor at a maturation stage prior to V(D)J rearrangement that undergoes branching evolution. Consequently, at single-cell resolution we observed considerable clonal tiding under selective therapeutic pressure. T-cell receptor next-generation sequencing suggested a highly biased usage of TRBV20-1 gene segments as part of multiple antigen receptor rearrangements per patient. The predominance of TRBV20-1 was found across all major T-cell lymphoma subtypes analyzed. This suggested that this particular V gene - independently of complementarity-determining region 3 configuration - may represent a driver of malignant transformation. Together, our data indicate that T-cell lymphomas are derived from immature lymphoid precursors and display considerable intratumoral heterogeneity that may provide the basis for relapse and resistance in these hard-to-treat cancers.