Mentz, Michael; Keay, William; Strobl, Carolin Dorothea; Antoniolli, Martina; Adolph, Louisa; Heide, Michael; Lechner, Axel; Haebe, Sarah; Osterode, Elisa; Kridel, Robert; Ziegenhain, Christoph; Wange, Lucas Esteban; Hildebrand, Johannes Adrian; Shree, Tanaya; Silkenstedt, Elisabeth; Staiger, Annette M; Ott, German; Horn, Heike; Szczepanowski, Monika; Richter, Julia; Levy, Ronald; Rosenwald, Andreas; Enard, Wolfgang; Zimber-Strobl, Ursula; von Bergwelt-Baildon, Michael; Hiddemann, Wolfgang; Klapper, Wolfram; Schmidt-Supprian, Marc; Rudelius, Martina; Bararia, Deepak; Passerini, Verena; Weigert, Oliver     «

Mentz, Michael; Keay, William; Strobl, Carolin Dorothea; Antoniolli, Martina; Adolph, Louisa; Heide, Michael; Lechner, Axel; Haebe, Sarah; Osterode, Elisa; Kridel, Robert; Ziegenhain, Christoph; Wange, Lucas Esteban; Hildebrand, Johannes Adrian; Shree, Tanaya; Silkenstedt, Elisabeth; Staiger, Annette M; Ott, German; Horn, Heike; Szczepanowski, Monika; Richter, Julia; Levy, Ronald; Rosenwald, Andreas; Enard, Wolfgang; Zimber-Strobl, Ursula; von Bergwelt-Baildon, Michael; Hiddemann, Wolfgang; Klap...     »

The 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 (TFH) 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 (STAT6MUT) 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 STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT 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 STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.      «

The 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 (TFH) 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 (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showe...     »