Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.
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.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Uri
U
Rozovski
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Ji Yuan
JY
Wu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
David M
DM
Harris
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Zhiming
Z
Liu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Ping
P
Li
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Inbal
I
Hazan-Halevy
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Alessandra
A
Ferrajoli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Jan A
JA
Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Susan
S
O'Brien
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Nitin
N
Jain
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Srdan
S
Verstovsek
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
William G
WG
Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Michael J
MJ
Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Zeev
Z
Estrov
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D011947:Receptors, Antigen, B-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C044203:anti-IgM; D014443:Tyrosine; C507924:JAK2 protein, human; D053614:Janus Kinase 2