Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma

Cancer Cell. 2015 Apr 13;27(4):516-32. doi: 10.1016/j.ccell.2015.03.006.

Abstract

A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.

Publication types

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

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Janus Kinase 1 / genetics
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Mice
  • Mutant Chimeric Proteins / genetics
  • Mutant Chimeric Proteins / metabolism
  • NF-kappa B / genetics
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Receptor Protein-Tyrosine Kinases / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • TYK2 Kinase / genetics

Substances

  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Mutant Chimeric Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Ros1 protein, mouse
  • Jak1 protein, mouse
  • Janus Kinase 1
  • TYK2 Kinase
  • Tyk2 protein, mouse