Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

Abstract

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 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 in vitro and in vivo.

Mutations leading to constitutive active gp130/JAK1/STAT3 pathway

“…Mutations were found in up to 70% of T-LGL and 30-40% of NK-LGL leukemia patients [50,[77][78][79]. Mutations of STAT3 were also identified in 5% of cutaneous forms of ALCL (cALCL) and 10% of ALK-negative ALCL [52]. Interestingly, in 7% of ALK-negative ALCL mutations of STAT3 and JAK1 occurred concomitantly.…”

“…Interestingly, in 7% of ALK-negative ALCL mutations of STAT3 and JAK1 occurred concomitantly. Functional tests of JAK1 and STAT3 mutants showed that individual aberrations could cooperate when co-expressed [52]. The mutations detected in leukemia and lymphoma patients are located in exons 20 and 21 in the SH2 domain of STAT3.…”

“…In this hematological neoplasm the most frequently mutated amino acid, G1097, is situated in the tyrosine kinase domain. This residue is sitting on the surface of the molecule, and it might modulate protein-protein interactions [52].…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Reports on patient mutation sequencing analyses of various T-cell lymphoma subtypes frequently include the JAK/STAT pathway, where JAK1, JAK3, STAT3 , and STAT5B are predominantly mutated to cause hyperactivation [64,70,75–78]. Importantly, ALK − ALCL is associated with STAT3 activation [64] and recurrent, somatic activating mutations in the closely related STAT5B gene were reported.…”

“…Importantly, ALK − ALCL is associated with STAT3 activation [64] and recurrent, somatic activating mutations in the closely related STAT5B gene were reported. The STAT5B N642H mutation occurs with the highest frequency in PTCL, whereby most mutations cluster in the SH 2 and C-terminal transactivation domain [70,75,78–82].…”