PARP14 is a novel target in STAT6 mutant follicular lymphoma

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 ; Bergwelt-Baildon, Michael von; Hiddemann, Wolfgang; Klapper, Wolfram ; Schmidt-Supprian, Marc; Rudelius, Martina; Bararia, Deepak; Passerini, Verena und Weigert, Oliver (2022): PARP14 is a novel target in STAT6 mutant follicular lymphoma. In: Leukemia, Bd. 36, Nr. 9: S. 2281-2292

Abstract

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 (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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0887-6924
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892