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

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

  1. Xiangao Huang1,*,
  2. Maurizio Di Liberto1,*,
  3. David Jayabalan1,2,
  4. Jun Liang1,
  5. Scott Ely1,
  6. Jamieson Bretz3,
  7. Arthur L. Shaffer III4,
  8. Tracey Louie1,
  9. Isan Chen5,
  10. Sophia Randolph5,
  11. William C. Hahn6,
  12. Louis M. Staudt4,
  13. Ruben Niesvizky2,
  14. Malcolm A. S. Moore7, and
  15. Selina Chen-Kiang1,3
  1. Departments of 1Pathology and Laboratory Medicine and
  2. 2Medicine, and
  3. 3Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY;
  4. 4Metabolism Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD;
  5. 5Pfizer Oncology, San Diego, CA;
  6. 6Broad Institute of Harvard and the Massachusetts Institute of Technology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and
  7. 7Memorial Sloan-Kettering Cancer Center, New York, NY


Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

  • Submitted March 7, 2012.
  • Accepted June 6, 2012.
View Full Text