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Myeloma

Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis

Leukemia volume 16, pages 127–134 (2002)Cite this article

Abstract

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20–25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40–45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.

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Acknowledgements

The authors thank Dr Lei Leu for assistance in performing the Northern blot analyses, and Margaret Rogers and Emma Pehovaz for expert technical assistance. We thank James Lampros for assistance with manuscript preparation. This work was supported in part by grant RO1-GM55985 from the National Institute of General Medicine, Bethesda, MD and grants ACS FRA-425 from the American Cancer Society, Atlanta, GA, and Fogarty TWO2297.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA

    MS Kulkarni & ME Williams

  2. Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA, USA

    JL Daggett & TP Bender

  3. Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    WM Kuehl

  4. Department of Internal Medicine, New York Hospital–Cornell Medical Center, New York, NY, USA

    PL Bergsagel

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Kulkarni, M., Daggett, J., Bender, T. et al. Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 16, 127–134 (2002). https://doi.org/10.1038/sj.leu.2402328

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