Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression

Maren Feist, Philipp Schwarzfischer, Paul Heinrich, Xueni Sun, Judith Kemper, Frederike von Bonin, Paula Perez-Rubio, Franziska Taruttis, Thorsten Rehberg, Katja Dettmer, Wolfram Gronwald, Jörg Reinders, Julia C. Engelmann, Jan Dudek, Wolfram Klapper, Lorenz Trümper, Rainer Spang, Peter J. Oefner and Dieter Kube ()
Additional contact information
Maren Feist: University Medical Centre Göttingen
Philipp Schwarzfischer: Network BMBF eBio MMML MYC-SYS
Paul Heinrich: University of Regensburg
Xueni Sun: University of Regensburg
Judith Kemper: University Medical Centre Göttingen
Frederike von Bonin: University Medical Centre Göttingen
Paula Perez-Rubio: Network BMBF eMed MMML-Demonstrators
Franziska Taruttis: Network BMBF eBio MMML MYC-SYS
Thorsten Rehberg: University of Regensburg
Katja Dettmer: University of Regensburg
Wolfram Gronwald: Network BMBF eBio MMML MYC-SYS
Jörg Reinders: University of Regensburg
Julia C. Engelmann: Network BMBF eBio MMML MYC-SYS
Jan Dudek: University Medical Centre Göttingen
Wolfram Klapper: Network BMBF eBio MMML MYC-SYS
Lorenz Trümper: University Medical Centre Göttingen
Rainer Spang: Network BMBF eBio MMML MYC-SYS
Peter J. Oefner: University of Regensburg
Dieter Kube: University Medical Centre Göttingen

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYClow cells depends on glutaminolysis. By 13C- and 15N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology.

Date: 2018
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DOI: 10.1038/s41467-018-03803-x

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