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Next Article  Blood, 15 September 2000, Vol. 96, No. 6, pp. 2005-2011 PLENARY PAPER Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3 Chiharu Kawamura, Masahiro Kizaki, Kenji Yamato, Hideo Uchida, Yumi Fukuchi, Yutaka Hattori, Takeyoshi Koseki, Tatsuji Nishihara, and Yasuo Ikeda From the Division of Hematology, Keio University School of Medicine, Tokyo; the Department of Molecular Cellular Oncology/Microbiology, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo; the Department of Oral Science, National Institute of Infectious Disease, Tokyo; and the Department of Oral Microbiology, Kyushu Dental College, Kitakyushu, Japan. Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)- superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21CIP1/WAF1 and p27KIP1) and caused hypophosphorylation of retinoblastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-xL; however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-xL and by cell-cycle arrest through the up-regulation of p21CIP1/WAF1 and p27KIP1 and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. We conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Frost, Y. Shi, B. Hoang, J. Gera, and A. 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