Activation of the B-cell receptor successively activates NF-kappa B and STAT3 in chronic lymphocytic leukemia cells

作者：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^*

来源：International Journal of Cancer, 2017, 141(10): 2076-2081.

DOI：10.1002/ijc.30892

• nuclear factor B
• signal transducer and activator of transcription 3
• phosphorylation
• chronic lymphocytic Leukemia

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-kappa B. Using an electromobility shift assay, we found that incubation with IgM antibodies for 4 or 18 hr, but not 15 min, increased NF-kappa B DNA-binding of CLL cells and increased binding was translated to increased transcriptional activity. Hence, 42% of the 83 NF-kappa B target genes were constitutively expressed in all CLL cells prior to any inducible stimuli. However, activation of the BCR increased the number of NF-kappa B 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-kappa B can be further enhanced by the BCR and that the BCR-induced activation of the JAK/STAT3 pathway depends on the NF-kappa B induced production of IL-6.

• 出版日期2017-11-15