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  • Review Article
  • Published:

Molecular pathogenesis of T-cell leukaemia and lymphoma

Nature Reviews Immunology volume 8, pages 380–390 (2008)Cite this article

Key Points

  • T-cell acute lymphoblastic leukaemia (T-ALL) is a paediatric leukaemia associated with distinct clinical and biological characteristics. Historically linked with a poor prognosis, T-ALL represents approximately 15% and 25% of cases of newly diagnosed ALL in children and adults, respectively.

  • Abnormal karyotypes are identified in approximately 50% of T-ALL cases, which is less than is found in other ALL types. In 35% of T-ALL cases, the T-cell receptor loci are involved in translocations, probably occurring at the stage of T-cell differentiation when V(D)J recombination takes place.

  • Recently, it has been found that more than 50% of cases of T-ALL have activating mutations in the key regulator of T-cell fate NOTCH1.

  • Much of our current understanding of the molecular basis of T-cell malignancies has come from a detailed analysis of mouse models expressing oncogenes and carrying the translocations observed in the human disease.

  • It is currently accepted that Notch1 mutations can induce T-cell transformation through multiple signalling pathways (such as the MYC and nuclear factor-κB (NF-κB) pathways) that alter cell survival, proliferation and metabolism.

  • Oncogenic Notch1 is regulated by the ubiquitin–proteasome machinery. More specifically, nuclear Notch1 is ubiquitylated by the E3 ligase FBW7. T-ALL NOTCH1 mutations create mutant forms of the protein that is unable to recognize FBW7.

  • FBW7 can act as a tumour suppressor in T-ALL. It is inactivated by point mutations in a large fraction of T-ALL cases. T-cell-specific deletion of the Fbw7 gene in mice leads to the induction of aggressive T-cell tumours.

  • Although current treatment protocols have improved the overall outcome for patients with T-ALL, a significant number of patients remain at a high risk for relapse, and few patients survive when the disease recurs. The newly acquired knowledge of the molecular pathology of the disease will facilitate the design of novel targeted therapies.

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is induced by the transformation of T-cell progenitors and mainly occurs in children and adolescents. Although treatment outcome in patients with T-ALL has improved in recent years, patients with relapsed disease continue to have a poor prognosis. It is therefore important to understand the molecular pathways that control both the induction of transformation and the treatment of relapsed disease. In this Review, we focus on the molecular mechanisms responsible for disease induction and maintenance. We also compare the physiological progression of T-cell differentiation with T-cell transformation, highlighting the close relationship between these two processes. Finally, we discuss potential new therapies that target oncogenic pathways in T-ALL.

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Figure 1: Stages of haematopoiesis and T-cell development and T-cell-leukaemia-related oncogenes.
Figure 2: Physiological and proposed oncogenic Notch1 signalling pathways.
Figure 3: Mechanism of T-ALL oncogene recognition and degradation by FBW7.

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Acknowledgements

We thank W. Carroll, B. Mar and the members of the Aifantis laboratory for stimulating discussions and help with the preparation of the manuscript. Our work has been supported by the US National Institutes of Health (RO1CA105129), the American Cancer Society (RSG0806801), the Edward Mallinckrodt, Jr Foundation, the Sidney Kimmel Foundation for Cancer Research, The Cancer Research Institute, The Penelope London Fund, The Friedman Fund for Childhood Leukemia, and the G&P Foundation for Cancer Research. S.B. is supported by the New York University Molecular Oncology and Immunology training grant (T32 CA-09161) and by an American Society of Haematology scholar award. We apologize for any omissions of key citations due to space constraints.

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Authors and Affiliations

  1. Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, 10016, New York, USA

    Iannis Aifantis, Elizabeth Raetz & Silvia Buonamici

  2. New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, 10016, New York, USA

    Iannis Aifantis & Silvia Buonamici

  3. Department of Pediatrics, New York University School of Medicine, 160 East 32nd Street, New York, 10016, New York, USA

    Elizabeth Raetz

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  1. Iannis Aifantis
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  2. Elizabeth Raetz
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  3. Silvia Buonamici
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Correspondence to Iannis Aifantis.

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Deletions that cannot be detected with standard cytogenetic analysis.

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(Pre-TCR). A receptor that is expressed on pre-T cells. It is formed by a TCR β-chain paired with a surrogate TCR-α chain (known as the invariant pre-Tα protein). The receptor complex includes CD3 proteins and transduces signals that allow further T-cell development.

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Aifantis, I., Raetz, E. & Buonamici, S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol 8, 380–390 (2008). https://doi.org/10.1038/nri2304

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