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

Summary 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 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.