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ACUTE LYMPHOBLASTIC LEUKEMIA

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T-ALL

Leukemia volume 38, pages 491–501 (2024)Cite this article

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Abstract

T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of TAL1 or LYL1 in T cell progenitors, or inactivation of E2A, is sufficient to predispose mice to develop T-ALL. How E2A suppresses thymocyte transformation is currently unknown. Here, we show that early deletion of E2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion of E2a prevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2A suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymocyte competition suppresses leukemogenesis.

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Fig. 1: Early hematopoietic deletion of E2a predisposes mice to T-ALL and alters thymocyte development.
Fig. 2: HSC-, but not DN3-deletion of E2a alters oncogenic gene expression in DP thymocytes from 4-week-old mice.
Fig. 3: VcKO DP thymocytes show increased gene dysregulation in 8-week-old DPs compared to 4-week-old DPs.
Fig. 4: Wild-type thymocytes compete with VcKO thymocytes to limit leukemogenesis and alter DP gene expression.
Fig. 5: Leukemia latency in TPT chimeric mice is associated with WT competitor chimerism.

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Data availability

The RNA-seq data presented in this paper are available through the Gene Expression Omnibus database under accession number GSE234609 and are available at the following URL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE234609. Other data in the paper will be made available upon reasonable request.

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Acknowledgements

We thank members of the Kee laboratory, S. Dias, and A. Melnick for helpful discussions and S. Liang for technical assistance. We thank the University of Chicago Genomics Facility (RRID: SCR_019196) and Cytometry and Antibody Technology Facility (RRID: SCR_017760).

Funding

This work was funded by the National Institutes of Health grants R21 AI119894, R01 AI107213, the Janet Rowley Fund from the University of Chicago Comprehensive Cancer Center, and a Team Science award from the Biological Science Division of the University of Chicago to BLK. GP was supported by T32 AI007090. The University of Chicago Genomics Facility and Cytometry and Antibody Technology Facility receive financial support from the Cancer Center Support Grant (P30 CA014599), and the Animal Resource Center.

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Authors and Affiliations

  1. Committee on Immunology, University of Chicago, Chicago, IL, 60637, USA

    Geoffrey Parriott, Rosemary E. Morman & Barbara L. Kee

  2. Department of Pathology, University of Chicago, Chicago, IL, 60637, USA

    Emma Hegermiller, Rosemary E. Morman, Cameron Frank & Barbara L. Kee

  3. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60657, USA

    Caner Saygin, Wendy Stock & Barbara L. Kee

  4. Department of Biochemistry and Molecular Genetics, Northwestern Feinberg School of Medicine, Chicago, IL, USA

    Elizabeth T. Bartom & Barbara L. Kee

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Contributions

GP designed, performed, and interpreted experiments and analyzed RNA-seq data, EH, REM and CF maintained mice, performed and analyzed experiments, and had essential intellectual input, CS and WS provided valuable advice and edited the manuscript, ETB performed RNA-seq analysis and edited the manuscript, BLK conceived of the project, designed and interpreted experiments, and provided funding for the project. GP and BLK wrote the manuscript.

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Correspondence to Barbara L. Kee.

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Parriott, G., Hegermiller, E., Morman, R.E. et al. Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T-ALL. Leukemia 38, 491–501 (2024). https://doi.org/10.1038/s41375-023-02123-4

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