Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells

• Published in: Blood 2014-06, Vol.123 (24), p.3797-3802
• Main Authors: Rozovski, Uri, Wu, Ji Yuan, Harris, David M., Liu, Zhiming, Li, Ping, Hazan-Halevy, Inbal, Ferrajoli, Alessandra, Burger, Jan A., O’Brien, Susan, Jain, Nitin, Verstovsek, Srdan, Wierda, William G., Keating, Michael J., Estrov, Zeev
• Format: Article
• Language: English
• Subjects: Antibodies, Anti-Idiotypic - pharmacology; Brief Report; Humans; Janus Kinase 2 - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocyte Activation - physiology; Lymphoid Neoplasia; Phosphorylation - drug effects; Receptors, Antigen, B-Cell - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Tumor Cells, Cultured; Tyrosine - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-10-534073

In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined. •Stimulation of the BCR activates JAK2 and STAT3 in CLL cells.•The JAK1/2 inhibitor ruxolitinib induces apoptosis of CLL cells.