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) STAT3? and STAT3? at codon 206 and constructed stable cell lines by lentiviral transfection of STAT3?(WT), STAT3?(M206K), STAT3?(WT) and STAT3?(M206K) plasmids. The mutation was found to increase STAT3 phosphorylation in STAT3? mutant cell lines with no effect on the STAT3? mutant cell line. Transcriptional activation was also increased in the STAT3? mutant cells compared with STAT3? WT cells as detected by a luciferase reporter assay. Moreover, STAT3?(M206K) mutant cells were resistant to JAK2 pathway inhibition compared to STAT3? 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.

SUBMITTER: Hu G 

PROVIDER: S-EPMC3701620 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature