Activating STAT6 mutations in follicular lymphoma

Abstract

• FL-associated STAT6 mutations hyperactivate the IL-4/JAK/STAT6 axis.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. (Blood. 2015;125(4):668-679)

Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations

“…29,30 STAT6 mutations in follicular lymphoma were reported to be mostly activating, with a hot spot at amino acid 419. 16 Herein, we demonstrate STAT6 mutations in the majority of the cases of this diffuse variant of nodal follicular lymphoma (80%), where five cases bore the aa419 hot spot mutation. This finding suggests a potential importance of the IL-4/ JAK/STAT6 pathway in this variant.…”

“…Overall then, nine cases of the follicular lymphoma variant had deletion and/or mutation of TNFRSF14. In conventional follicular lymphoma, STAT6 mutations have been reported in about 11% of cases, 16 but in this variant, 9 of 11 cases (480%) bore mutations. Across the nine cases, seven different single nucleotide variants were detected including two in each of two cases.…”

“…Five cases of the nine exhibited mutations within codon 419 (Asp), a reported hot spot for mutation in follicular lymphoma. 16 Of the remaining four cases, three had variants previously observed in lymphoid neoplasms according to COSMIC (http://cancer. sanger.ac.uk/cosmic).…”

“…Recently, STAT6 mutations have been demonstrated in a minority of follicular lymphoma cases, 11-12% in follicular lymphoma and 23% in transformed follicular lymphoma, where it was unclear whether STAT6 mutation was associated with differing histologies or t(14;18) status. 10,[15][16] Perhaps P-STAT6 immunohistochemistry could serve as surrogate for STAT6 mutation in this follicular lymphoma variant, although the specificity of this assertion requires a more comprehensive study. Of note, we stained 33 cases of conventional follicular lymphoma for P-STAT6 and CD23 and did not see an association between CD23 expression and nuclear P-STAT6 immunoreactivity, at least for conventional follicular lymphoma (unpublished data).…”

“…When examining the mutational profile of this CD23+ follicular lymphoma variant for genes frequently involved in mature B-cell neoplasms, it was evident that for most genes, mutation frequencies were comparable with those observed in conventional follicular lymphoma, but others were relatively underrepresented (KMT2D, TP53) or enriched (TNFRSF14, CREBBP, and STAT6). 7,8,10,15,16 Such a mutational profile could be useful in distinguishing such cases in a diagnostic setting. For instance, at least two of the three CD10 − cases, particularly difficult to separate from nodal marginal zone lymphoma, carried STAT6 mutations.…”