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Functional regulation of D-type cyclins by insulin-like growth factor-I and serum in multiple myeloma cells

Janet Glassford1, Neil Rabin, Eric W-F Lam

  • 1Department of Haematology, University College London, London, UK. j.glassford@ucl.ac.uk

British Journal of Haematology
|September 28, 2007
PubMed

Insights

D-type cyclins are functionally regulated in multiple myeloma (MM), with expression linked to disease progression. Their activity, influenced by specific genetic translocations, drives cell cycle progression in MM patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • D-type cyclin genes are dysregulated in multiple myeloma (MM), but their functional impact on proliferation and disease progression remains unclear.
  • Previous studies show gene expression doesn't correlate with MM progression, necessitating protein-level investigation.

Purpose of the Study:

  • To investigate the protein expression and functional regulation of D-type cyclins and cell cycle regulators in MM.
  • To determine how IgH translocations influence D-type cyclin function and response to microenvironmental stimuli.

Main Methods:

  • Analysis of protein expression of D-type cyclins (D1, D2), CDKs (4, 6), p27(Kip1), p18(INK4C), and pRb in human MM cell lines and primary CD138(+) plasma cells (PCs).
  • Assessing the functional consequences of cyclin D2 and D1 expression, particularly in relation to IgH translocations (t(14;16), t(4;14), t(11;14)) and exogenous stimuli (fetal calf serum, IGF-I).

Main Results:

  • Cyclins D1, D2, CDK4, CDK6, p27(Kip1), p18(INK4C), and pRb were absent in normal PCs but heterogeneously expressed in MM cells, correlating with disease activity.
  • Cyclins D1 and D2 formed complexes with CDK4/CDK6, leading to pRb phosphorylation and cell cycle progression.
  • Cyclin D2, upregulated by translocations and growth factors, drove cell cycle progression, sometimes inversely with p27(Kip1); cyclin D1-mediated progression was less stimulus-dependent.

Conclusions:

  • D-type cyclins are functionally regulated in MM, with aberrant expression linked to disease progression.
  • The specific IgH translocations influence the responsiveness of D-type cyclins to microenvironmental growth factors.
  • This study provides the first evidence of functional regulation and differential responsiveness of D-type cyclins in MM.

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