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Mentz, M. ; Keay, W.* ; Strobl, C.D.* ; Antoniolli, M.* ; Adolph, L.* ; Heide, M.* ; Lechner, A.* ; Haebe, S.* ; Osterode, E.* ; Kridel, R.* ; Ziegenhain, C.* ; Wange, L.E.* ; Hildebrand, J.A.* ; Shree, T.* ; Silkenstedt, E.* ; Staiger, A.M.* ; Ott, G.* ; Horn, H.* ; Szczepanowski, M.* ; Richter, J.* ; Levy, R.* ; Rosenwald, A.* ; Enard, W.* ; Zimber-Strobl, U. ; von Bergwelt-Baildon, M.* ; Hiddemann, W.* ; Klapper, W.* ; Schmidt-Supprian, M.* ; Rudelius, M.* ; Bararia, D.* ; Passerini, V.* ; Weigert, O.*

PARP14 is a novel target in STAT6 mutant follicular lymphoma.

Leukemia 36, 2281–2292 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 36, Issue: , Pages: 2281–2292 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)