Activating STAT6 mutations in follicular lymphoma

• Published in: Blood Vol. 125; no. 4; pp. 668 - 679
• Main Authors: Yildiz, Mehmet, Li, Hongxiu, Bernard, Denzil, Amin, Nisar A., Ouillette, Peter, Jones, Siân, Saiya-Cork, Kamlai, Parkin, Brian, Jacobi, Kathryn, Shedden, Kerby, Wang, Shaomeng, Chang, Alfred E., Kaminski, Mark S., Malek, Sami N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.2015; American Society of Hematology
• Subjects: Active Transport, Cell Nucleus - genetics; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; HEK293 Cells; Humans; Interleukin-4 - genetics; Interleukin-4 - metabolism; Janus Kinases - genetics; Janus Kinases - metabolism; Lymphoid Neoplasia; Lymphoma, Follicular - genetics; Lymphoma, Follicular - metabolism; Lymphoma, Follicular - pathology; Mutation, Missense; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphorylation - genetics; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Transcriptional Activation - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-06-582650

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 FLs. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell–based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) –induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboring mutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4–induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis. •FL-associated STAT6 mutations hyperactivate the IL-4/JAK/STAT6 axis.