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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-04-13

AUTHORS

Clemens Grabher, Harald von Boehmer, A. Thomas Look

ABSTRACT

Key PointsT-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. More... »

PAGES

347-359

References to SciGraph publications

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  • Journal

    TITLE

    Nature Reviews Cancer

    ISSUE

    5

    VOLUME

    6

    Related Patents

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrc1880

    DOI

    http://dx.doi.org/10.1038/nrc1880

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1050959167

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16612405


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    37 schema:description Key PointsT-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.
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