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Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

Nature Reviews Cancer volume 6, pages 347–359 (2006)Cite this article

Key Points

  • T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive blood cancer that affects about 1,500 people per year in the United States. Significant advances have been made in the development of effective therapies for this otherwise rapidly fatal disease, which is most common in children and adolescents.

  • T-ALL can be classified into at least five different subtypes based on the activation of specific T-ALL oncogenes and associated gene-expression profiles that correlate with the stage of arrest in T-cell development.

  • The NOTCH1 gene is expressed in haematopoietic stem cells (HSCs) and controls several steps in thymocyte specification and differentiation. Chromosomal alterations that juxtapose a truncated, activated form of Notch1 (TAN1) with the T-cell receptor-β (TCRB) locus occur in less than 1% of all T-ALL cases.

  • Somatic activating mutations of Notch1 have been identified in more than 50% of all T-ALL cases and are found in all previously defined T-ALL subtypes. One set of mutations destabilizes the Notch heterodimerization domain, probably facilitating ligand-independent pathway activation, whereas mutations that disrupt the intracellular PEST (polypeptide enriched in proline, glutamate, serine and threonine) domain might function by increasing the half-life of transcriptionally active intracellular Notch 1 (ICN1).

  • The high prevalence of Notch1 mutations in T-ALL, and the dependence of T-ALL cases on Notch-1-pathway activation for unrestricted proliferation render this protein an excellent candidate for pharmacological intervention with γ-secretase inhibitors.

  • Studies of Notch 1 in the induction of T-ALL, using murine and zebrafish T-ALL models, might lead to the discovery of pharmacological inhibitors that specifically target other components in the Notch 1 pathway.

  • Emerging knowledge of the specific gene-expression profiles associated with T-ALL subtypes, the important function of Notch 1 in T-cell leukaemogenesis, and the development of novel, specific inhibitors should stimulate the development of disease-specific treatments that increase survival rates and improve the quality of life of patients with T-ALL.

Abstract

The chromosomal translocation t(7;9) in human T-cell acute lymphoblastic leukaemia (T-ALL) results in deregulated expression of a truncated, activated form of Notch 1 (TAN1) under the control of the T-cell receptor-β (TCRB) locus. Although TAN1 efficiently induces T-ALL in mouse models, t(7;9) is present in less than 1% of human T-ALL cases. The recent discovery of novel activating mutations in NOTCH1 in more than 50% of human T-ALL samples has made it clear that Notch 1 is far more important in human T-ALL pathogenesis than previously suspected.

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Figure 1: Distribution of genomic aberrations and Notch1 mutations in paediatric T-ALL.
Figure 2: The Notch signalling pathway.
Figure 3: Notch 1 receptors in T-cell development.
Figure 4: Notch 1 receptor mutations in human T-cell acute lymphoblastic leukaemia.
Figure 5: Correlation between gene-expression profiles and stage of thymocyte differentiation.

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Acknowledgements

We thank A. A. Ferrando and W. S. Pear for permission to modify their original figures and J. Gilbert for editorial review. C.G. is supported by the Lady Tata Memorial Trust. Research in the Look and von Boehmer laboratories is supported by a programme project grant from the National Cancer Institute.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Clemens Grabher & A. Thomas Look

  2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Harald von Boehmer

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  1. Clemens Grabher
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Correspondence to A. Thomas Look.

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DATABASES

National Cancer Institute

acute lymphoblastic leukaemia

chronic myeloid leukaemia

FURTHER INFORMATION

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Glossary

Double-negative

Immature thymocytes that do not express CD4 or CD8 cell-surface markers and have not yet undergone gene rearrangement to produce a functional TCR. Double negative thymocytes can be divided up into 4 subsets (DN1–DN4) that reflect their maturation status.

Episomal elements

Extra-chromosomal DNA (such as a plasmid). Amplification of a DNA segment followed by circularization can result in the generation of episomal DNA (for example the NUP214–ABL1 gene fusion).

Double-positive

Thymocytes expressing both the CD4 and CD8 cell-surface markers after successful rearrangement of a functional TCRβ chain.

γ-Secretase inhibitor

Ligand binding to Notch 1 initiates two successive proteolytic cleavages (S2 and S3). The S2 cleavage allows access of the γ-secretase complex, which is responsible for the second proteolytic cleavage (S3). This cleavage liberates the intracellular domain of Notch 1 (ICN1), which translocates the nucleus to activate gene transcription. So, inhibition of the γ-secretase complex prevents the activation of Notch signalling pathways.

PEST domain

A motif that contains the amino-acids proline (P), glutamic acid (E), serine (S) and threonine (T) that is involved in targeting proteins for degradation through the ubiquitin-26S proteosome pathway.

V-D-J recombination

The TCRB locus contains V, D and J segments, similar to the immunoglobulin heavy-chain locus, that are rearranged into diverse combinations that increase the repertoire of antigens recognized by the T-cell receptor.

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Grabher, C., von Boehmer, H. & Look, A. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 6, 347–359 (2006). https://doi.org/10.1038/nrc1880

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