AbstractThe variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (T_FH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6^MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6^MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6^MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6^MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6^MUT lymphoma cells and in STAT6^MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6^MUT but not STAT6^WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6^MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6^MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6^MUT FL.