TY - JOUR
T1 - A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells
AU - Hideshima, Teru
AU - Mitsiades, Constantine
AU - Ikeda, Hiroshi
AU - Chauhan, Dharminder
AU - Raje, Noopur
AU - Gorgun, Gullu
AU - Hideshima, Hiromasa
AU - Munshi, Nikhil C.
AU - Richardson, Paul G.
AU - Carrasco, Daniel R.
AU - Anderson, Kenneth C.
PY - 2010/5/6
Y1 - 2010/5/6
N2 - 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-α (TNF-α) also triggered Bcl-6, but independently of STAT3, whereas IκB kinaseβ inhibitor down-regulated TNF-α-induced Bcl-6, indicating that the canonical nuclear factor-κB pathway mediates TNF-α-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-κB pathways and that targeting Bcl-6, either directly or via these cascades, inhibits MM cell growth in the BM milieu.
AB - 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-α (TNF-α) also triggered Bcl-6, but independently of STAT3, whereas IκB kinaseβ inhibitor down-regulated TNF-α-induced Bcl-6, indicating that the canonical nuclear factor-κB pathway mediates TNF-α-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-κB pathways and that targeting Bcl-6, either directly or via these cascades, inhibits MM cell growth in the BM milieu.
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U2 - 10.1182/blood-2010-02-270082
DO - 10.1182/blood-2010-02-270082
M3 - Article
C2 - 20228272
AN - SCOPUS:77952559263
SN - 0006-4971
VL - 115
SP - 3772
EP - 3775
JO - Blood
JF - Blood
IS - 18
ER -