The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

J Exp Med. 2012 Aug 27;209(9):1537-51. doi: 10.1084/jem.20120904. Epub 2012 Aug 13.

Abstract

Splenic marginal zone lymphoma (SMZL) is a B cell malignancy of unknown pathogenesis, and thus an orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, we show that the SMZL exome carries at least 30 nonsilent gene alterations. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ∼20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL; these include NOTCH1, SPEN, and DTX1. We also noted mutations in other signaling pathways normally involved in MZ B cell development, suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis of ∼60% SMZL. These findings have direct implications for the treatment of SMZL patients, given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Chromatin Assembly and Disassembly
  • Exome
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Humans
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Mutation*
  • NF-kappa B / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Receptor, Notch1 / genetics
  • Receptor, Notch2 / genetics*
  • Receptor, Notch2 / metabolism
  • Signal Transduction
  • Splenic Neoplasms / genetics*
  • Splenic Neoplasms / metabolism
  • Splenic Neoplasms / pathology

Substances

  • Homeodomain Proteins
  • NF-kappa B
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Nuclear Proteins
  • Receptor, Notch1
  • Receptor, Notch2
  • SPEN protein, human