Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

O E Olsen; K F Wader; K Misund; T K Våtsveen; T B Rø; A K Mylin; I Turesson; B F Størdal; S H Moen; T Standal; A Waage; A Sundan; T Holien

doi:10.1038/bcj.2014.16

Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

Blood Cancer J. 2014 Mar 21;4(3):e196. doi: 10.1038/bcj.2014.16.

Authors

O E Olsen¹, K F Wader², K Misund¹, T K Våtsveen¹, T B Rø³, A K Mylin⁴, I Turesson⁵, B F Størdal¹, S H Moen¹, T Standal⁶, A Waage⁷, A Sundan⁶, T Holien¹

Affiliations

¹ KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway.
² 1] KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway [2] Department of Oncology, St Olav's University Hospital, Trondheim, Norway.
³ 1] KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway [2] Department of Pediatrics, St Olav's University Hospital, Trondheim, Norway.
⁴ Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁵ Department of Hematology and Coagulation Disorders, Skane University Hospital, Malmö, Sweden.
⁶ 1] KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway [2] CEMIR (Centre of Molecular Inflammation Research), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ 1] KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway [2] Department of Hematology, St Olav's University Hospital, Trondheim, Norway.

Abstract

Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8-809) compared with healthy controls (median 110 pg/ml, range 8-359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma.