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.

journal_name

Blood

journal_title

Blood

authors

Yildiz M,Li H,Bernard D,Amin NA,Ouillette P,Jones S,Saiya-Cork K,Parkin B,Jacobi K,Shedden K,Wang S,Chang AE,Kaminski MS,Malek SN

doi

10.1182/blood-2014-06-582650

subject

Has Abstract

pub_date

2015-01-22 00:00:00

pages

668-79

issue

4

eissn

0006-4971

issn

1528-0020

pii

blood-2014-06-582650

journal_volume

125

pub_type

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