PARP14 is a novel target in STAT6 mutant follicular lymphoma.

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 (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.

• Authors: Michael Mentz, William Keay, Carolin Dorothea Strobl, Martina Antoniolli, Louisa Adolph, Michael Heide, Axel Lechner, Sarah Haebe, Elisa Osterode, Robert Kridel, Christoph Ziegenhain, Lucas Esteban Wange, Johannes Adrian Hildebrand, Tanaya Shree, Elisabeth Silkenstedt, Annette M Staiger, German Ott, Heike Horn, Monika Szczepanowski, Julia Richter, Ronald Levy, Andreas Rosenwald, Wolfgang Enard, Ursula Zimber-Strobl, Michael von Bergwelt-Baildon, Wolfgang Hiddemann, Wolfram Klapper, Marc Schmidt-Supprian, Martina Rudelius, Deepak Bararia, Verena Passerini, Oliver Weigert
• Journal: Leukemia (Leukemia) Vol. 36 Issue 9 Pg. 2281-2292 (09 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 35851155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• STAT6 Transcription Factor
• STAT6 protein, human
• Interleukin-4
• PARP14 protein, human
• Poly(ADP-ribose) Polymerases

Topics

• Humans
• Immunohistochemistry
• Interleukin-4
• Lymphoma, B-Cell
• Lymphoma, Follicular
• Poly(ADP-ribose) Polymerases
• STAT6 Transcription Factor
• Transcriptional Activation
• Tumor Microenvironment