title: A novel missense (M206K) STAT3 mutation in diffuse large B cell lymphoma deregulates STAT3 signaling.
abstract: Persistent STAT3 activation has been found in activated B-cell like diffuse large B cell tumors (DLBCL). To investigate whether genetic mutations play a role in aberrant STAT3 signaling in DLBCL, we bi-directionally sequenced all 24 exons of the STAT3 gene in DLBCL tumors (n = 40). We identified 2 novel point mutations in 2 separate (2/40; 5%) patients at exon 7 and 24. Point mutation 2552G>A was a silent mutation in the stop codon. Another heterozygous mutation 857T>A encoded a methionine substitution by lysine at codon 206 (M206K) in the coiled-coil domain of STAT3. We performed site directed mutagenesis to mutate wild type (WT) STAT3α and STAT3β at codon 206 and constructed stable cell lines by lentiviral transfection of STAT3α(WT), STAT3α(M206K), STAT3β(WT) and STAT3β(M206K) plasmids. The mutation was found to increase STAT3 phosphorylation in STAT3α mutant cell lines with no effect on the STAT3β mutant cell line. Transcriptional activation was also increased in the STAT3α mutant cells compared with STAT3α WT cells as detected by a luciferase reporter assay. Moreover, STAT3α(M206K) mutant cells were resistant to JAK2 pathway inhibition compared to STAT3α WT cells. These results indicate that missense mutations in STAT3 increase signaling through the JAK/STAT pathway. JAK2 inhibitors may be useful in the patient with this STAT3 mutation as well as those with pathway activation by other mechanisms.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Guangzhen
authors.initials: G
authors.lastname: Hu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005091:Exons; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008156:Luciferases; C507924:JAK2 protein, human; D053614:Janus Kinase 2