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Molecular Diagnostics

TCF3::HLF-positive B-ALL: integrated clinical and molecular characterization of 34 cases from a single-center cohort

British Journal of Cancer (2026)Cite this article

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Abstract

Background

TCF3::HLF-positive B-cell acute lymphoblastic leukemia (B-ALL) is a rare, highly aggressive subtype with historically poor outcomes. Despite its classification as a distinct entity, its clinical and molecular landscape remains poorly understood.

Methods

This study presents a single-center cohort of 34 TCF3::HLF-positive B-ALL patients, providing comprehensive clinical and molecular characterization by integrating clinical data, treatment responses, survival outcomes, whole-transcriptome sequencing (WTS), targeted sequencing, and flow cytometry.

Results

TCF3::HLF accounted for 1.59% of B-ALL cases. Three fusion isoforms were identified, with Isoform III likely arising from alternative splicing. No significant clinical or transcriptomic differences were observed between Isoform I and II. The 5-year overall survival (OS) was 35.2%. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved OS and event-free survival (p < 0.0001), while chimeric antigen receptor T-cell (CAR-T) therapy facilitated allo-HSCT but lacked durable efficacy. RAS pathway mutations were prevalent (85.7%), and CD33 expression was frequent (79.4%), suggesting potential therapeutic targets. WTS analysis revealed dysregulation of epithelial-mesenchymal transition, coagulation, and immune pathways.

Conclusions

TCF3::HLF-positive B-ALL represents an ultra-high-risk leukemia requiring allo-HSCT for long-term remission. CAR-T serves as a bridge to transplantation, while RAS and CD33-directed therapies warrant further investigation. These findings provide critical insights into disease biology and potential treatment.

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Fig. 1: Structures of TCF3-related fusions reported in this study.
Fig. 2: Structural and transcriptomic features of TCF3::HLF isoforms.
Fig. 3: Gene mutations identified in TCF3::HLF-, TCF3::PBX1-, and TCF3::ZNF384-positive B-ALL cases.
Fig. 4: Clinical course of the 34 TCF3::HLF-positive B-ALL patients.
Fig. 5: Survival analysis of TCF3::HLF-positive B-ALL patients.
Fig. 6: Transcriptomic and pathway dysregulation in TCF3::HLF-positive B-ALL.

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Data availability

For original data, please contact starliu@pku.edu.cn

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Acknowledgements

The authors express their sincere gratitude to the patients and their families for their participation in this study. This work was supported by the Langfang Science and Technology Research and Development Program (Grant No. 2023013154).

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Author notes

  1. These authors contributed equally: Xue Chen, Xiaoli Ma.

Authors and Affiliations

  1. Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China

    Xue Chen, Yang Zhang, Panxiang Cao, Jiaqi Chen, Xiaosu Zhou, Siyuan Liu & Hongxing Liu

  2. Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China

    Xue Chen, Xiaoli Ma, Lili Yuan, Fang Wang, Yang Zhang, Jiancheng Fang, Panxiang Cao, Tong Wang, Jiaqi Chen & Hongxing Liu

  3. Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China

    Min Xiong

  4. Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China

    Junfang Yang & Xian Zhang

  5. Division of Pathology and Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, China

    Hongxing Liu

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Contributions

HL designed and supervised the study and revised the manuscript. XC and XM conducted comprehensive data analysis and drafted the article. LY, FW, YZ, and JC analyzed clinical data. JF, PC, XZ (Zhou), and SL performed molecular and bioinformatic analyses. TW conducted cytogenetic analysis. MX, JY, and XZ (Zhang) were responsible for patient management and provided clinical specimens. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Hongxing Liu.

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Chen, X., Ma, X., Yuan, L. et al. TCF3::HLF-positive B-ALL: integrated clinical and molecular characterization of 34 cases from a single-center cohort. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03370-9

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