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(American Journal of Pathology. 2004;165:71-81.)
© 2004 American Society for Investigative Pathology

Overexpression of PDZK1 within the 1q12-q22 Amplicon Is Likely To Be Associated with Drug-Resistance Phenotype in Multiple Myeloma

Jun Inoue^*, Takemi Otsuki, Akira Hirasawa^*, Issei Imoto^*, Yoshinobu Matsuo^¶, Shiroh Shimizu^||, Masafumi Taniwaki^** and Johji Inazawa^*

From the Department of Molecular Cytogenetics,^* Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo; Theranostics Research Center, Otsuka Pharmaceutical Company Limited, Tokushima; the Department of Hygiene, Kawasaki Medical School, Okayama; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama; Fujisaki Cell Center,^¶ Hayashibara Biochemical Laboratories Incorporated, Okayama; the Department of Internal Medicine,^|| Shimane Prefectual Central Hospital; the Division of Hematology and Oncology, Department of Medicine,^** Kyoto Prefectural University of Medicine, Kyoto; and the Center of Excellence on Molecular Destruction and Reconstitution of Tooth and Bone [J.Ina], Tokyo Medical and Dental University, Tokyo, Japan

We investigated DNA copy number aberrations in 37 cell lines derived from multiple myelomas (MMs) using comparative genomic hybridization, and 11 (29.7%) showed high-level gain indicative of gene amplification at 1q12-q22. A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications. Among them PDZK1 showed amplification and consequent overexpression in the MM cell lines. Amplification of PDZK1 was observed in primary cases of MM as well. MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications. Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin. Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor.

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