CHARACTERIZATION OF P16(INK4A) EXPRESSION IN MULTIPLE-MYELOMA AND PLASMA-CELL LEUKEMIA

Loss of pl6(INK4A) (p16) expression is frequently associated with the development of epithelial and lymphoid malignancies, However, the freq uency and significance of p16 abnormalities in multiple myeloma (MM) a nd the more aggressive phase of plasma cell leukemia (PCL) have not be en well defined, Accordingly, the goal of this study was to define the expression and function of p16 in fresh samples of MM and PCL, We fou nd that p16 protein was highly expressed in primary MM cells, although it was undetectable in fresh samples of PCL. Additionally, p16 protei n was also absent in four of four MM-derived cell lines, To determine the mechanism for p16 underexpression in PCL and MM-derived cell lines , we performed PCR analysis to evaluate both gene deletion and the pre sence of methylation, Interestingly, the p16 gene was present and meth ylated in all patient PCL cells and MM cell lines, whereas it was unme thylated in patient MM cells and normal B cells, Furthermore, treatmen t with the demethylating agent 5-deoxyazacytidine or p16 retrofection restored p16 protein expression and induced G(1), growth arrest in pat ient PCL cells and MM cell lines, These results suggest that inactivat ion of the p16 gene by methylation may be associated with decreased gr owth control and the development of PCL in a subset of patients with M M.