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

• Published in: Leukemia Vol. 16; no. 1; pp. 127 - 134
• Main Authors: KULKARNI, M. S, DAGGETT, J. L, BENDER, T. P, KUEHL, W. M, BERGSAGEL, P. L, WILLIAMS, M. E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 2002; Nature Publishing Group
• Subjects: Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Biological and medical sciences; Cell Cycle; Cell Cycle Proteins; Cell death; Cell Division; Cyclin D1 - physiology; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p18; Cyclin-Dependent Kinases; Enzyme Inhibitors; Gene Deletion; Genes; Genes, Tumor Suppressor; Genotype; Hematologic and hematopoietic diseases; Humans; Internal medicine; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Mantle-Cell - pathology; Medical sciences; Medicine; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Oncology; Pathogenesis; Penicillin; Phosphorylation; Protein-Serine-Threonine Kinases - physiology; Recombinant Fusion Proteins - physiology; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology; Tumors; New York; United States > US; Human; Immunopathology; Pathogenesis; Gene overexpression; Malignant hemopathy; Cyclin D1; Myeloma; Carcinogenesis; Cyclin dependent kinase inhibitor; Immunoglobulinopathy; Gene; Lymphoproliferative syndrome; Cell cycle; Apoptosis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2402328

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.