TCF3::hlf-positive b-ALL: Largest cohort study to date reveals unique molecular landscape and treatment challenges

作者：Xue Chen, Xiaoli Ma, Lili Yuan, Fang Wang, Yang Zhang, Jiancheng Fang, Panxiang Cao, Tong Wang, Min Xiong, Junfang Yang, Xian Zhang, Jiaqi Chen, Xiaosu Zhou, Siyuan Liu, Hongxing Liu · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-34 · 被引用次数：1 · 研究领域：Acute Lymphoblastic Leukemia research、Chronic Myeloid Leukemia Treatments、CAR-T cell therapy research

Abstract Background: TCF3::HLF-positive B-cell acute lymphoblastic leukemia (B-ALL) represents one of the most aggressive and treatment-refractory subtypes of ALL. It is characterized by the t(17;19)(q22;p13) translocation generating the TCF3::HLF fusion, leading to impaired B-cell differentiation, chemoresistance, and early relapse. Despite its classification as a distinct entity in the 2022 WHO and ICC frameworks, comprehensive clinical and molecular characterization remains limited due to its extreme rarity. Methods: We analyzed 34 consecutive TCF3::HLF-positive B-ALL patients diagnosed between 2012 and 2024 at a single leukemia center, representing the largest cohort to date. Multi-dimensional profiling included clinical data, immunophenotyping, karyotyping, gene mutation screening of 86 leukemia-related genes, and whole transcriptome sequencing (WTS). Comparisons were made with 129 TCF3::PBX1- and 25 TCF3::ZNF384-positive B-ALL cases to contextualize clinical outcomes and molecular features. Results: TCF3::HLF accounted for 1.6% of all B-ALL cases (n=2,136), with a pediatric predominance (88%, median age 11 years). Three fusion isoforms were identified, but Isoform III was always co-detected with Isoform II and showed significantly lower read support, suggesting an alternatively spliced variant rather than a distinct event. Immunophenotypically, CD33 and/or CD13 expression was present in 88% of cases, implying partial myeloid lineage priming. Karyotyping revealed a high ...