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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 (T FH ) are critical components of the FL TME. Binding of IL-4 to I...
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Published in: | Leukemia 2022-09, Vol.36 (9), p.2281-2292 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/s41375-022-01641-x |