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; Dieter Kube

doi:10.1038/s41467-018-03803-x

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

Nat Commun. 2018 Apr 17;9(1):1514. doi: 10.1038/s41467-018-03803-x.

Authors

Maren Feist^{1

2}, Philipp Schwarzfischer^{2

3}, Paul Heinrich^{3

4}, Xueni Sun^{3

4}, Judith Kemper¹, Frederike von Bonin¹, Paula Perez-Rubio^{4

5}, Franziska Taruttis^{2

5}, Thorsten Rehberg⁵, Katja Dettmer^{3

4}, Wolfram Gronwald^{2

3

4}, Jörg Reinders³, Julia C Engelmann^{2

4

5

6}, Jan Dudek⁷, Wolfram Klapper^{2

4

8}, Lorenz Trümper^{1

2

4}, Rainer Spang^{2

4

5}, Peter J Oefner³, Dieter Kube^{9

10

11}

Affiliations

¹ Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany.
² Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.
³ Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.
⁴ Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.
⁵ Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.
⁶ NIOZ Royal Netherlands Institute for Sea Research and Utrecht University, 1790 AB, Den Burg, The Netherlands.
⁷ Institute of Biochemistry, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany.
⁸ Department of Pathology, Hematopathology Section, UKSH Campus Kiel, 24105, Kiel, Germany.
⁹ Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany. dieter.kube@med.uni-goettingen.de.
¹⁰ Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany. dieter.kube@med.uni-goettingen.de.
¹¹ Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany. dieter.kube@med.uni-goettingen.de.

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 MYC^low 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aspartate Aminotransferase, Mitochondrial / genetics*
Aspartate Aminotransferase, Mitochondrial / metabolism
B-Lymphocytes / metabolism
Cell Line, Tumor
Cell Proliferation / genetics
Cell Transformation, Neoplastic / genetics
Cellular Reprogramming / genetics
Cohort Studies
Female
Gene Expression Regulation, Neoplastic*
Humans
Lymphoma, Large B-Cell, Diffuse / genetics*
Lymphoma, Large B-Cell, Diffuse / mortality
Lymphoma, Large B-Cell, Diffuse / pathology
Male
Phosphorylation
Prognosis
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
STAT3 Transcription Factor / metabolism*
Signal Transduction / genetics
Survival Analysis
Transcription Factor RelA / metabolism*

Substances

MYC protein, human
Proto-Oncogene Proteins c-myc
RELA protein, human
STAT3 Transcription Factor
STAT3 protein, human
Transcription Factor RelA
Aspartate Aminotransferase, Mitochondrial