Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma

Cancer Sci. 2009 May;100(5):920-6. doi: 10.1111/j.1349-7006.2009.01130.x.


Signaling through the Notch1 receptor has a pivotal role in early thymocyte development. Gain of Notch1 function results in the development of T-cell acute lymphoblastic leukemia in a number of mouse experimental models, and activating Notch1 mutations deregulate Notch1 signaling in the majority of human T-cell acute lymphoblastic leukemias. Notch2, another member of the Notch gene family, is preferentially expressed in mature B cells and is essential for marginal zone B-cell generation. Here, we report that 5 of 63 (approximately 8%) diffuse large B-cell lymphomas, a subtype of mature B-cell lymphomas, have Notch2 mutations. These mutations lead to partial or complete deletion of the proline-, glutamic acid-, serine- and threonine-rich (PEST) domain, or a single amino acid substitution at the C-terminus of Notch2 protein. Furthermore, high-density oligonucleotide microarray analysis revealed that some diffuse large B-cell lymphoma cases also have increased copies of the mutated Notch2 allele. In the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors show increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B-cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles
  • Base Sequence
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Dosage / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Interferon Regulatory Factors / metabolism
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neprilysin / metabolism
  • Proto-Oncogene Proteins c-bcl-6
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism*


  • BCL6 protein, human
  • DNA, Complementary
  • DNA-Binding Proteins
  • Interferon Regulatory Factors
  • NOTCH2 protein, human
  • Proto-Oncogene Proteins c-bcl-6
  • Receptor, Notch2
  • interferon regulatory factor-4
  • Neprilysin