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Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS

Leukemia volume 17, pages 2533–2535 (2003)Cite this article

TO THE EDITOR

Pathogenesis of cancer involves a stepwise accumulation of genetic alterations that disrupt either the normal machinery of cell proliferation or its regulation by the activation of cellular oncogenes or inactivation of tumor suppressor genes.1 Cellular proliferation is mediated by progression through the cell cycle, where two cell cycle checkpoints are located at G1S and G2M. Quiescent cells in G0 phase contain hypophosphorylated RB, which sequesters the transcription factor E2F. Upon activation by mitogens, upregulation of D-type cyclins results in activation of cyclin-dependent kinases (CDK), namely CDK4 and CDK6, resulting in phosphorylation of RB. Hyperphosphorylated RB results in release of E2F, which activates transcription of S1-specific genes, and irreversible commitment to cell cycle progression. Negative regulatory elements to the cell cycle progression include the INK4 (p15, p16, p18 and p19) and the CIP/KIP (p21CIP, p27KIP1 and p57KIP2) families of proteins that give rise to cell cycle arrest.1 P15, p16, p18 and p19 are coined INK4 family CDK inhibitors (CKI) as they share similar functional domains (ankyrin repeats for protein–protein interactions) that render them capable of competing with cyclin D for CDK4 and 6, and thus inhibition of CDKs 4 and 6.

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Acknowledgements

We thank Professor Eshhar, Department of Immunology, Weizmann Institute of Science, Israel, for provision of AF10 cell line; and Department of Pathology, Queen Mary Hospital, for the diagnoses; and Kadoorie Foundation for the funding support.

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  1. University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong

    C S Chim, T K Fung & R Liang

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  1. C S Chim
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Correspondence to C S Chim.

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Chim, C., Fung, T. & Liang, R. Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS. Leukemia 17, 2533–2535 (2003). https://doi.org/10.1038/sj.leu.2403133

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