Abstract
A subset of ALK− anaplastic large cell lymphomas exhibit constitutive activation of STAT3 signaling.
Major finding: A subset of ALK− anaplastic large cell lymphomas exhibit constitutive activation of STAT3 signaling.
Concept: Oncogenic JAK1/STAT3 mutations and transcription regulator–tyrosine kinase fusions were identified.
Impact: JAK inhibitors impair the growth of ALK− anaplastic large cell lymphomas in preclinical models.
Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma involving peripheral T cells and is often characterized by translocations of anaplastic lymphoma kinase (ALK) that lead to activation of the STAT3 pathway. However, the mechanisms underlying oncogenic transformation in ALK fusion–negative (ALK−) ALCL, which is associated with increased mortality, have not been defined. Using integrative genomic sequencing, Crescenzo, Abate, Lasorsa, and colleagues identified recurrent nonsynonymous somatic mutations in JAK1 and STAT3 specifically in systemic ALK− ALCL tumors, including co-occurring mutations in both genes in a subset of tumors. JAK1 and STAT3 mutants exhibited oncogenic activity and synergized to constitutively activate STAT3 phosphorylation and induce a STAT3-driven transcriptional program that included upregulation of activating transcription factor 3. Importantly, treatment with the JAK1/JAK2 inhibitor ruxolitinib diminished the growth of mutant STAT3–expressing cells both in vitro and in patient-derived ALK− ALCL tumorgrafts in vivo. Furthermore, whole-transcriptome sequencing analysis revealed the presence of chimeric transcripts in 4 of 18 ALK− ALCLs in the absence of JAK1 or STAT3 mutations, resulting in fusions of the N-terminus of the transcription factor NFκB2 or transcriptional repressors such as nuclear receptor corepressor 2 (NCOR2) with the intracytoplasmic domain of the tyrosine kinases ROS1 or TYK2. NFκB2–tyrosine kinase fusions were transcriptionally active, resulting in a unique gene expression signature and constitutive activation of the JAK/STAT3 signaling pathway. In addition, expression of NFκB2–tyrosine kinase or NCOR2–ROS1 fusions induced oncogenic transformation and promoted tumor growth in a STAT3-dependent manner, and, similar to expression of JAK1 and STAT3 mutants, rescued the viability of ALK+ ALCL cells following ALK inhibition. These results suggest that STAT3 activation may be a common oncogenic driver in ALCL and support the idea that pharmacologic inhibition of JAK/STAT3 signaling may be therapeutically beneficial in patients with ALK− ALCL.