TY - JOUR
T1 - Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma
AU - Chen, Lijuan
AU - Wang, Siqing
AU - Zhou, Yiming
AU - Wu, Xiaosong
AU - Entin, Igor
AU - Epstein, Joshua
AU - Yaccoby, Shmuel
AU - Xiong, Wei
AU - Barlogie, Bart
AU - Shaughnessy, John D.
AU - Zhan, Fenghuang
PY - 2010/1/7
Y1 - 2010/1/7
N2 - Tumor-bone marrow microenvironment interactions in multiple myeloma (MM) are documented to play crucial roles in plasma-cell growth/survival. In vitro coculture of MM cells with osteoclasts supported cell survival and significantly down-regulated JUN expression. JUN expression in myeloma cells from late-stage and high-risk MM was significantly lower than in plasma cells from healthy donors, monoclonal gammopathy of undetermined significance, smoldering MM, and low-risk MM; patients with low-JUN-expressing MM cells had earlier disease-related deaths. JUN overexpression in MM cells induced cell death and growth inhibition and up-regulated expression of early growth response protein 1 (EGR-1), whose low expression also carried unfavorable clinical implications. EGR-1 knockdown in MM cells abrogated JUN overexpression-induced MM cell death and growth inhibition, indicating that EGR-1 acts directly downstream of JUN. JUN modulates myeloma cell apoptosis through interacting with EGR-1, which down-regulates Survivin and triggers caspase signaling. Importantly, high JUN or EGR-1 expression was associated with improved outcome in Total Therapy 3, in which bortezomib is given throughout therapy, versus Total Therapy 2, in which bortezomib is given only at relapse. Consistently, JUN or EGR-1 knockdown in cultured MM cells enhanced their resistance to bortezomib, demonstrating the crucial role of low JUN/EGR-1 expression in MM resistance to bortezomib.
AB - Tumor-bone marrow microenvironment interactions in multiple myeloma (MM) are documented to play crucial roles in plasma-cell growth/survival. In vitro coculture of MM cells with osteoclasts supported cell survival and significantly down-regulated JUN expression. JUN expression in myeloma cells from late-stage and high-risk MM was significantly lower than in plasma cells from healthy donors, monoclonal gammopathy of undetermined significance, smoldering MM, and low-risk MM; patients with low-JUN-expressing MM cells had earlier disease-related deaths. JUN overexpression in MM cells induced cell death and growth inhibition and up-regulated expression of early growth response protein 1 (EGR-1), whose low expression also carried unfavorable clinical implications. EGR-1 knockdown in MM cells abrogated JUN overexpression-induced MM cell death and growth inhibition, indicating that EGR-1 acts directly downstream of JUN. JUN modulates myeloma cell apoptosis through interacting with EGR-1, which down-regulates Survivin and triggers caspase signaling. Importantly, high JUN or EGR-1 expression was associated with improved outcome in Total Therapy 3, in which bortezomib is given throughout therapy, versus Total Therapy 2, in which bortezomib is given only at relapse. Consistently, JUN or EGR-1 knockdown in cultured MM cells enhanced their resistance to bortezomib, demonstrating the crucial role of low JUN/EGR-1 expression in MM resistance to bortezomib.
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UR - http://www.scopus.com/inward/citedby.url?scp=74949107707&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-03-210526
DO - 10.1182/blood-2009-03-210526
M3 - Article
C2 - 19837979
AN - SCOPUS:74949107707
SN - 0006-4971
VL - 115
SP - 61
EP - 70
JO - Blood
JF - Blood
IS - 1
ER -