Recent advances on NOTCH signaling in T-ALL

Curr Top Microbiol Immunol. 2012;360:163-82. doi: 10.1007/82_2012_232.

Abstract

NOTCH1 receptor signaling plays a central role in T-cell lineage specification and in supporting the growth and proliferation of immature T-cell progenitors in the thymus during lymphoid development. In T-cell acute lymphoblastic leukemia (T-ALL), a tumor resulting from the malignant transformation of T-cell progenitors, aberrant and constitutively active NOTCH1 signaling triggered by activating mutations in the NOTCH1 gene contributes to oncogenic transformation and is a hallmark of this disease. Most notably, small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease. In addition, a number of emerging anti-NOTCH therapeutic strategies including anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs and glucocorticoids, have recently been proposed. Finally, the identification of NOTCH1 mutations in solid tumors and chronic lymphocytic leukemias has increased even further the clinical relevance of NOTCH signaling as a therapeutic target in human cancer. Here we review our current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 in T-ALL and the therapeutic and prognostic implications of NOTCH1 mutations in T-ALL.

Publication types

  • Review

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Antibodies / therapeutic use
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Drug Therapy, Combination
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Leukemic / immunology*
  • Humans
  • Molecular Targeted Therapy
  • Mutation
  • Peptides / therapeutic use
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*

Substances

  • Antibodies
  • Enzyme Inhibitors
  • NOTCH1 protein, human
  • Peptides
  • Receptor, Notch1
  • Amyloid Precursor Protein Secretases