APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status

Blood. 2011 Jan 20;117(3):890-901. doi: 10.1182/blood-2010-01-264424. Epub 2010 Aug 13.

Abstract

A proliferation-inducing ligand (APRIL) promotes survival and drug resistance in multiple myeloma (MM) cell lines. We studied the effect of APRIL on cell-cycle behavior in primary MM cells and correlated our findings with D-type cyclin expression by immunohistochemistry and/or Western blotting. In MM cases, expressing cyclin D2 APRIL significantly increased the percentage of CD138(+) cells in S + G(2)/M phase (from 8.4% ± 1.9% to 14.3% ± 2.6%, n = 15, P < .01), whereas a lesser effect was seen in cases expressing cyclin D1 (n = 18). Cell-cycle response to APRIL was most marked for cyclin D2-expressing cases with IgH translocations (P < .01) and was accompanied by increased expression of cyclin D2, CDK4, CDK6, and phospho-retinoblastoma protein. Cell-cycle proteins in cyclin D1(+) cells were not modulated by APRIL. Surface expression of B-cell maturation antigen and transmembrane activator and calcium-modulating cyclophilin ligand interactor was not significantly different between cyclin D1(+) and D2(+) MM cells. We observed activation of nuclear factor-κB and PI3-kinase pathways in response to APRIL in both cyclin D1(+) and D2(+) MM cells. In conclusion, APRIL stimulates G(1)/S progression in cyclin D2(+) MM cells bearing IgH translocations but has minimal effect on cyclin D1(+) cells, suggesting MM cells from different cyclin D/translocation classes rely on different mechanisms for cell-cycle re-entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Marrow Cells / metabolism
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Culture Media / chemistry
  • Culture Media / pharmacology
  • Cyclin D / metabolism*
  • Cyclin D2 / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Multiple Myeloma / blood
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Protein Transport / drug effects
  • Syndecan-1 / metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / pharmacology*

Substances

  • Cell Cycle Proteins
  • Culture Media
  • Cyclin D
  • Cyclin D2
  • SDC1 protein, human
  • Syndecan-1
  • TNFSF13 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 13