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

Abstract

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.

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

“…This is a likely scenario. However, a study by Inoue et al (35) examined a number of cell lines derived from multiple myelomas with high-level gene amplification at 1q12-q22 corresponding, in part, to PDZK1 with a subsequent overexpression at the protein level. The PDZK1-overexpressing cell lines exhibited resistance to melphalan-, cisplatinand vincristin-induced death compared with cell lines with no PDZK1.…”

Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma

“…Consistent with this, a large number Chromosome 1q21 copy change and prognosis in myeloma R Fonseca et al of candidate genes in the 1q21 region (e.g., BCL9, MCL1, CKS1B and MUC1) have been pathogenically implicated in MM and other malignancies. 9,[28][29][30][31][32][33][34][35][36][37] More recently, integrated analysis of high-resolution array comparative genomic hybridization and GEP identified a high priority minimal region of DNA copy number change on 1q21. This 10 Mb region contain several genes including the aforementioned CSK1B, BCL9 and MCL1.…”

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

“…However, 8 out of 24 overexpressed genes did not belong to any of the above-mentioned functional groups. Although two genes, PDZK1 and MLLT11, were clearly relevant to cancer as both have been proposed as a candidate oncogene in diverse haematological malignancies (Busson-Le Coniat et al, 1999;Inoue et al, 2004;Tse et al, 2004), six were more difficult to relate to cancer. Three corresponded to genetic determinants of genetic syndromes (MTMR, DISC1, MTX1) and the three others bore functions with no obvious link to cancer (NENF, ENSA, TARBP1).…”