Blood Journal
Leading the way in experimental and clinical research in hematology

Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications

  1. Jana Jakubikova1,
  2. Sophia Adamia2,
  3. Maria Kost-Alimova3,
  4. Steffen Klippel1,
  5. David Cervi1,
  6. John F. Daley2,
  7. Dana Cholujova4,
  8. Sun-Young Kong1,
  9. Merav Leiba1,
  10. Simona Blotta1,
  11. Melissa Ooi1,
  12. Jake Delmore1,
  13. Jacob Laubach1,
  14. Paul G Richardson1,
  15. Jan Sedlak4,
  16. Kenneth C Anderson1, and
  17. Constantine S Mitsiades1,*
  1. 1 Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA, United States;
  2. 2 Department of Medicine, Harvard Medical School, Boston, MA, United States;
  3. 3 Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, United States;
  4. 4 Cancer Research Institute, Department of Tumor Immunology, Bratislava, Slovakia
  1. * Corresponding author; email: constantine_mitsiades{at}dfci.harvard.edu

Abstract

Recurrence of multiple myeloma after therapy suggests the presence of tumor-initiating sub-populations. In our study, we performed flow cytometry-based Hoechst 33342 staining to evaluate the existence of a MM population with "stem-like" features known as side population (SP) cells. SP cells exhibit substantial heterogeneity in MM cell lines and primary MM cells; express CD138 antigen in MM cell lines; display higher mRNA expression and functional activity of ABCG2 transporter and had higher proliferation index compared to non-SP cells. We observed evidence for clonogenic potential of SP cells, as well as ability of SP cells to regenerate original population. Moreover, SP cells revealed higher tumorigenicity compared to MP cells. Importantly, lenalidomide decreased the percentage and clonogenicity of SP cells; and also induced phosphorylation changes in Akt, GSK-3α/β, MEK1, c-Jun, p53 and p70S6K in SP cells. Adherence to bone marrow stromal cells (BMSCs) increased the percentage, viability, and proliferation potential of SP cells. Lenalidomide and thalidomide abrogated this stimulatory effect of BMSCs and significantly decreased percentage of SP cells. Our studies demonstrate novel mechanism of action of lenalidomide targeting SP fraction, providing the framework for new therapeutic strategies targeting subpopulations of MM cells including presumptive stem cells.

  • Submitted February 9, 2010.
  • Accepted October 10, 2010.