Activating STAT6 mutations in follicular lymphoma
| Autor: | Sami N. Malek, Hongxiu Li, Mehmet Yildiz, Si�n Jones, Brian Parkin, Peter Ouillette, Mark S. Kaminski, Alfred E. Chang, Nisar A. Amin, Kamlai Saiya-Cork, Shaomeng Wang, Denzil Bernard, Kerby Shedden, Kathryn Jacobi |
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| Rok vydání: | 2015 |
| Předmět: |
Transcriptional Activation
Immunology Mutant Active Transport Cell Nucleus Mutation Missense Follicular lymphoma Biology Biochemistry Transactivation Cell Line Tumor parasitic diseases medicine Humans Phosphorylation Lymphoma Follicular Gene Transcription factor Janus Kinases Cell Nucleus Lymphoid Neoplasia integumentary system HEK 293 cells Cell Biology Hematology Transfection respiratory system medicine.disease Molecular biology Neoplasm Proteins Lymphoma Gene Expression Regulation Neoplastic HEK293 Cells Cancer research Interleukin-4 STAT6 Transcription Factor Genome-Wide Association Study |
| Zdroj: | Blood. 125:668-679 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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