T Cell Acute Lymphoblastic leukemia/lymphoma: A Human Cancer Commonly Associated With Aberrant NOTCH1 Signaling

Curr Opin Hematol. 2004 Nov;11(6):426-33. doi: 10.1097/01.moh.0000143965.90813.70.

Abstract

Purpose of review: Although constitutively activated forms of the NOTCH1 receptor are potent inducers of T cell acute lymphoblastic leukemia/lymphoma when expressed in the bone marrow stem cells of mice, the known involvement of NOTCH1 in human T cell acute lymphoblastic leukemia/lymphoma has been restricted to very rare tumors associated with a (7;9) chromosomal translocation involving the NOTCH1 gene. This picture has changed dramatically in the past year with the discovery of frequent mutations involving NOTCH1 in human T cell acute lymphoblastic leukemia/lymphoma.

Recent findings: NOTCH1 point mutations, insertions, and deletions producing aberrant increases in NOTCH1 signaling are frequently present in both childhood and adult T cell acute lymphoblastic leukemia/lymphoma and are detected in tumors from all major molecular subtypes. These observations are particularly important in the light of experiments using human and murine T cell acute lymphoblastic leukemia/lymphoma cell lines indicating that NOTCH1 signals are required for sustained growth and, in a subset of lines, survival. This inference is based in part on experiments conducted with small molecule inhibitors of gamma-secretase, a protease required for normal NOTCH signal transduction and the activity of the mutated forms of NOTCH1 found commonly in human T cell acute lymphoblastic leukemia/lymphoma.

Summary: These findings support a central role for aberrant NOTCH signaling in the pathogenesis of human T cell acute lymphoblastic leukemia/lymphoma, and they provide a rationale for trials of NOTCH inhibitors, such as gamma-secretase antagonists, in this aggressive human malignancy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Endopeptidases / metabolism
  • Gene Expression Regulation, Leukemic / genetics*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Mutation*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Receptor, Notch1
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction* / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • NOTCH1 protein, human
  • Neoplasm Proteins
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Transcription Factors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human