Activating STAT6 mutations in follicular lymphoma
Menée sur 114 patients atteints d'un lymphome folliculaire, puis sur des lignées cellulaires, cette étude identifie, dans 11% des cas, la présence de mutations activant l'expression du gène STAT6
Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole exome sequencing (WES) of 23 highly purified FL cases and one transformed FL case and expanded findings to a combined total of 114 FL. We report recurrent mutations in the transcription factor STAT6 in 11% of FL and identify 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 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 uncovered that most FL-associated STAT6 mutants locate to the STAT6/DNA interface, potentially facilitating heightened interactions. Combined, the genetic and functional data strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis.
Blood 2014