DISEASE PROGRESSION IN PATIENTS WITH MULTIPLE-MYELOMA IS ASSOCIATED WITH A CONCURRENT ALTERATION IN THE EXPRESSION OF BOTH ONCOGENES AND TUMOR-SUPPRESSOR GENES AND CAN BE MONITORED BY THE ONCOPROTEIN PHENOTYPE

The dysregulation of specific oncogenes due to either mutation or acti vation has previously. been reported in a small number of patients wit h myeloma but the extent of oncogene dysregulation during the course o f the disease is not known. The oncoprotein phenotype of plasma cells in 146 bone marrow samples from 81 patients with multiple myeloma was determined by dual colour flow cytometry using a predetermined panel o f 8 monoclonal antibodies. High intensity CD38 expression was used to distinguish the plasma cell population and the cells were permeabilise d to detect intracellular antigen expression. In situ hybridization us ing biotinylated cDNA probes for c-myc and bcl-2 was used to determine mRNA expression and to validate the flow cytometric assay. The normal range of expression for each of 6 oncoproteins (c-myc, c-fos, c-neu, bcl-2, p-rns, p53 mutant) and 2 tumour suppressor gene products (p53 w ild and Rb) was determined in plasma cells from 33 normal bone marrows . Disease progression was associated with the concurrent abnormal expr ession of at least one oncogene and one tumour suppressor gene where a s stable disease was associated with a normal expression of at least o ne or both (chi(2) = 34.1; p < 0.001). At diagnosis there was a correl ation between serum beta 2 microglobulin and the concurrent overexpres sion of both an oncoprotein and a tumour suppressor gene product. Long itudinal studies of 33 different patients over 4 years, suggests that the progressive evolution of myeloma is a multistep process of genomic instability producing ongoing alterations in the expression of both o ncogenes and tumour suppressor genes.