Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma

  • Leukemia. 2015 Jan;29(1):207-17. doi: 10.1038/leu.2014.147.
M Hiasa  1 ,  J Teramachi  2 ,  A Oda  3 ,  R Amachi  4 ,  T Harada  3 ,  S Nakamura  3 ,  H Miki  3 ,  S Fujii  3 ,  K Kagawa  3 ,  K Watanabe  4 ,  I Endo  3 ,  Y Kuroda  5 ,  T Yoneda  6 ,  D Tsuji  7 ,  M Nakao  8 ,  E Tanaka  4 ,  K Hamada  9 ,  S Sano  8 ,  K Itoh  7 ,  T Matsumoto  3 ,  M Abe  3
Affiliations
  • 1. 1] Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [2] Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [3] Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 2. Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 3. Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 4. Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 5. Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
  • 6. Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN, USA.
  • 7. Department of Medicinal Biotechnology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 8. Department of Molecular Medicinal Chemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
  • 9. Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
PMID: 24787487 DOI: 10.1038/leu.2014.147
Abstract

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and Activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim Inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.

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