title: Activating STAT6 mutations in follicular lymphoma.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Mehmet
authors.initials: M
authors.lastname: Yildiz
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Nisar A
authors.initials: NA
authors.lastname: Amin
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.affiliation: Personal Genome Diagnostics, Baltimore, MD;
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Brian
authors.initials: B
authors.lastname: Parkin
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Jacobi
authors.affiliation: Department of Statistics, and.
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kaminski
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C508598:IL4 protein, human; D009363:Neoplasm Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D053612:Janus Kinases