A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells.
Constitutive B-cell lymphoma 6 (Bcl-6) expression was undetectable in multiple myeloma (MM) cell lines, except U266 cells. However, it was up-regulated by coculture with bone marrow (BM) stromal cell-culture supernatant (SCCS). Bcl-6 expression in patient MM cells in the BM was positive. Anti-interleukin-6 (IL-6)-neutralizing antibody significantly blocked SCCS-induced Bcl-6 in MM cells. Indeed, IL-6 strongly triggered Bcl-6 expression in MM cells, whereas Janus kinase inhibitor and STAT3 siRNA down-regulated Bcl-6. Tumor necrosis factor-alpha (TNF-alpha) also triggered Bcl-6, but independently of STAT3, whereas IkappaB kinasebeta inhibitor down-regulated TNF-alpha-induced Bcl-6, indicating that the canonical nuclear factor-kappaB pathway mediates TNF-alpha-induced Bcl-6 expression. Importantly, down-regulation of Bcl-6 by shRNA significantly inhibited MM cell growth in the presence of SCCS. Our results therefore suggest that Bcl-6 expression in MM cells is modulated, at least in part, via Janus kinase/STAT3 and canonical nuclear factor-kappaB pathways and that targeting Bcl-6, either directly or via these cascades, inhibits MM cell growth in the BM milieu.
Hideshima
Teru
T
Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Mitsiades
Constantine
C
Ikeda
Hiroshi
H
Chauhan
Dharminder
D
Raje
Noopur
N
Gorgun
Gullu
G
Hideshima
Hiromasa
H
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Carrasco
Daniel R
DR
Anderson
Kenneth C
KC
D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D057134:Antibodies, Neutralizing; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D053612:Janus Kinases