Nuclear topography of the 1q21 genomic region and Mcl-1 protein levels associated with pathophysiology of multiple myeloma
Chromosomal rearrangements and copy number variation are frequently observed in cancer cells, including multiple myeloma (MM). Karyotypic abnormalities seen in MM cells correlate with the disease stage and drug responses. Here, we investigate the nuclear arrangement of the 1q21 region; amplification of this region is an important diagnostic and prognostic marker of MM. We examined the lymphoblastoid cell line CD138(-) ARH-77, multiple myeloma CD138(+) MOLP-8 cells, and the CD138(+) bone marrow fraction of patients diagnosed with MM. In this experimental system, we observed that gamma-radiation and selected cytostatic drugs such as melphalan and dexamethasone did not significantly alter the nuclear radial arrangement of the 1q21 region and other relevant regions of chromosome 1. Similarly, conserved nuclear radial positioning after cytostatic treatment was observed for the c-myc,TP53, CCND1, and IgH loci. When analyzed Mcl-1, a protein encoded by a gene mapped to the 1q21 region, we found that the variant Mcl-1(s) is highly expressed in multiple myeloma MOLP-8 cells, but not in peripheral blood lymphocytes of healthy donors or lymphoblastoid ARH-77 cells; this is in contrast to the expression pattern of the Mcl-1(L) variant. On the basis of these observations we suggest that the 1q21 region is an important diagnostic marker of MM, particularly the gene encoding the Mcl-1(s) variant, which can be easily detected by western analysis.