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

The European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium Genetics-Driven Targeted Management of Lymphoid Malignancies

Research output: Contribution to journalArticle

190 Scopus citations

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 155 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 invitro and invivo.

Original languageEnglish (US)
Pages (from-to)516-532
Number of pages17
JournalCancer Cell
Volume27
Issue number4
DOIs
StatePublished - Apr 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    The European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium Genetics-Driven Targeted Management of Lymphoid Malignancies (2015). Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell, 27(4), 516-532. https://doi.org/10.1016/j.ccell.2015.03.006