Cell Cycle Progression of Chronic Lymphocytic Leukemia Cells Is Controlled by Cyclin D2, Cyclin D3, Cyclin-Dependent Kinase (Cdk) 4 and the CDK Inhibitor p27

Leukemia. 2002 Mar;16(3):327-34. doi: 10.1038/sj.leu.2402389.

Abstract

B-CLL cells are arrested in G0/early G1 phase of the cell cycle and are characterized by a marked hyporesponsiveness towards a variety of polyclonal B cell activators. We have previously demonstrated that costimulation with CpG-ODN and IL-2 can overcome this proliferative defect. Cyclin D3 is the principal D-type cyclin which mediates G1 progression in normal B cells, but in B-CLL cells both cyclin D2 and cyclin D3, were strongly upregulated upon stimulation. Both cyclins were associated with cdk4 but not with cdk6, which is the catalytic partner of D-type cyclins in normal B cells. Moreover, immune complexes consisting of cyclin D2 and cdk4 or cyclin D3 and cdk4 were both functional and phosphorylated the RB protein in vitro. The cell cycle inhibitor p27 plays a pivotal role in cell cycle progression of B lymphocytes and has been shown to be overexpressed in B-CLL cells. P27 was rapidly downregulated in B-CLL cells even when stimulated with a non-CpG-ODN or IL-2 alone, while only moderate regulation could be observed in normal B cells. Taken together, our findings demonstrate that regulation of early cell cycle progression differs between B-CLL cells and normal B cells. These findings do not only contribute to the understanding of B-CLL pathophysiology, but might ultimately lead to the identification of new therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / metabolism*
  • Cyclin D1 / metabolism
  • Cyclin D2
  • Cyclin D3
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / metabolism*
  • DNA Primers / chemistry
  • Drug Combinations
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Interleukin-2 / pharmacology
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Oligodeoxyribonucleotides / pharmacology
  • Phosphorylation
  • Precipitin Tests
  • Proto-Oncogene Proteins*
  • Retinoblastoma Protein / metabolism
  • Thymidine / metabolism
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Suppressor Proteins / metabolism*

Substances

  • CCND2 protein, human
  • CCND3 protein, human
  • CPG-oligonucleotide
  • Cell Cycle Proteins
  • Cyclin D2
  • Cyclin D3
  • Cyclins
  • DNA Primers
  • Drug Combinations
  • Interleukin-2
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Thymidine