Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma.
BACKGROUND
The deregulation of several transcription factors contribute to the aggressive course of mantle cell lymphoma. This study focuses on survival signals emanating from the tumor environment and involving the signal transducer and activator of transcription (STAT) 3 through cytokines or antigen recognition.


METHODS
Primary mantle cell lymphoma cells were isolated from 20 leukemic patients. The phosphorylation status of STAT3 was evaluated by immunoblottting and immunofluorescence, the levels of cytokine secretion by enzyme-linked immunosorbent assay and the cell survival signals by apoptosis and cell viability assays.


RESULTS
STAT3 was constitutively phosphorylated in the Jeko-1 mantle cell lymphoma cell line and in 14 out of 20 (70%) cases of leukemic mantle cell lymphoma as the result of an autocrine secretion of interleukin-6 and/or interleukin-10. In addition, B-cell receptor engagement resulted in an increase of both in vitro cell survival and STAT3 phosphorylation in primary mantle cell lymphoma cells. Inhibition of the Janus-activated kinase/STAT3 pathway increased spontaneous apoptosis and suppressed B-cell receptor-induced cell survival in all cases analyzed. The impact of in vitro exposure to the proteasome inhibitor bortezomib was next evaluated in primary mantle cell lymphoma cells. Bortezomib induced apoptosis and a decrease of both interleukin-6/interleukin-10 secretion and STAT3 phosphorylation. In addition, bortezomib inhibited B-cell receptor-triggered STAT3 phosphorylation and cell survival.


CONCLUSIONS
We demonstrated that STAT3 was activated in primary mantle cell lymphoma cells either constitutively through a cytokine autocrine loop or in response to B-cell receptor engagement, both processes leading to a survival signal inhibited by bortezomib. STAT3 appears, therefore, to play a pivotal role in mantle cell lymphoma and represents a promising therapeutic target.
Baran-Marszak
Fanny
F
INSERM U978, Bobigny, France.
Boukhiar
Mohand
M
Harel
Stéphanie
S
Laguillier
Christelle
C
Roger
Claudine
C
Gressin
Remy
R
Martin
Antoine
A
Fagard
Remi
R
Varin-Blank
Nadine
N
Ajchenbaum-Cymbalista
Florence
F
Ledoux
Dominique
D
D000368:Aged; D000369:Aged, 80 and over; D019898:Autocrine Communication; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D001897:Boronic Acids; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D011480:Protease Inhibitors; D011719:Pyrazines; D011947:Receptors, Antigen, B-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D000069286:Bortezomib; D053612:Janus Kinases