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 STAT3αWT, STAT3αM206K, STAT3βWT and STAT3βM206K 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, STAT3αM206K 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.
Highlights
Diffuse large B cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma
Modular structure indicates that this M206K STAT3 mutation is located near a nuclear localization signal (NLS) in the coiled-coil domain of STAT3 (Figure 1C)
We have previously demonstrated that JAK2 mutations are not the cause [9]; there have been few reports on the role of STAT3 mutations in lymphoma in general and DLBCL
Summary
Diffuse large B cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma. JAK2/STAT3 was shown to be highly activated in DLBCL patient samples and DLBCL cell lines [1], [2], [3]. We have demonstrated that elevated serum interleukin 10 (IL-10) is one cause for constitutive STAT3 activation [8]. Mutations missense mutations (which leads to amino acid changes) in JAK2 and STAT3 are another potential cause of STAT3 activation. Our lab has recently showed that there are no JAK2 activating missense mutations in DLBCL tumors [9]. 30% patients with chronic lymphoproliferative disorders of natural killer cells had STAT3 activating missense mutations [10]. STAT3 mutations have been described to activate STAT3 in a subset (40%) of patients with T-cell large granular lymphocytic leukemia [11]. The presence of STAT3 mutations in DLBCL tumors has recently described
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