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Activation of the B‐cell receptor successively activates NF‐κB and STAT3 in chronic lymphocytic leukemia cells
Author(s) -
Rozovski Uri,
Harris David M.,
Li Ping,
Liu Zhiming,
Jain Preetesh,
Veletic Ivo,
Ferrajoli Alessandra,
Burger Jan,
Thompson Philip,
Jain Nitin,
Wierda William,
Keating Michael J.,
Estrov Zeev
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30892
Subject(s) - breakpoint cluster region , stat3 , phosphorylation , b cell receptor , chronic lymphocytic leukemia , tyrosine phosphorylation , microbiology and biotechnology , signal transduction , cancer research , biology , antibody , janus kinase 2 , tyrosine kinase , b cell , chemistry , receptor , leukemia , immunology , biochemistry
In chronic lymphocytic leukemia (CLL) cells, both interleukin‐6 (IL‐6) and the B‐cell receptor (BCR) activate Janus kinase 2 (JAK2) and induce the phosphorylation of signal transduction and activator of transcription 3 (STAT3) on tyrosine 705 residues. However, whereas IL‐6 phosphorylates STAT3 within 15 min, stimulation of the BCR with anti‐immunoglobulin M (IgM) antibodies phosphorylates STAT3 in 2–4 hr. Here, we show that this process takes longer because it requires transcriptional activity of NF‐κB. Using an electromobility shift assay, we found that incubation with IgM antibodies for 4 or 18 hr, but not 15 min, increased NF‐κB DNA‐binding of CLL cells and increased binding was translated to increased transcriptional activity. Hence, 42% of the 83 NF‐κB target genes were constitutively expressed in all CLL cells prior to any inducible stimuli. However, activation of the BCR increased the number of NF‐κB target genes with detectable expression by 23%. Remarkably, prolonged incubation with anti‐IgM antibodies induced a time‐dependent transcription, production and secretion of IL‐6 protein. The IgM‐induced production of IL‐6 prompted the phosphorylation of STAT3 on tyrosine residues. This effect was inhibited by the JAK1/2 inhibitor of the JAK/STAT3 pathway ruxolitinib. Taken together, these results suggest that in CLL cells, constitutive tonic activation of NF‐κB can be further enhanced by the BCR and that the BCR‐induced activation of the JAK/STAT3 pathway depends on the NF‐κB induced production of IL‐6.