Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma

Haematologica. 2014 Dec;99(12):1834-45. doi: 10.3324/haematol.2014.106401. Epub 2014 Sep 5.

Abstract

Germinal center lymphoma is a heterogeneous human lymphoma entity. Here we report that constitutive activity of SHP2 (PTPN11) and its downstream kinase ERK is essential for the viability of germinal center lymphoma cells and disease progression. Mechanistically, SHP2/ERK inhibition impedes c-Myc transcriptional activity, which results in the repression of proliferative phenotype signatures of germinal center lymphoma. Furthermore, SHP2/ERK signaling is required to maintain the CD19/c-Myc loop, which preferentially promotes survival of a distinct subtype of germinal center lymphoma cells carrying the MYC/IGH translocation. These findings demonstrate a critical function for SHP2/ERK signaling upstream of c-Myc in germinal center lymphoma cells and provide a rationale for targeting SHP2 in the therapy of germinal center lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Germinal Center / metabolism
  • Germinal Center / pathology*
  • Humans
  • Immunoenzyme Techniques
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoprecipitation
  • Lymphoma / genetics
  • Lymphoma / metabolism
  • Lymphoma / pathology*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Translocation, Genetic / genetics*
  • Tumor Cells, Cultured

Substances

  • Immunoglobulin Heavy Chains
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA, Small Interfering
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11