MULTIPLE PATTERNS OF MDM-2 DEREGULATION IN HUMAN LEUKEMIAS - IMPLICATIONS IN LEUKEMOGENESIS AND PROGNOSIS

The human analogue of the mouse double minute-2 (MDM-2) protein binds to p53 protein and abrogates its tumor-suppressing activity. MDM-2 ove rexpression may represent an alternative mechanism to p53 mutation for escaping the p53-mediated growth control. Interestingly, multiple MDM -2 protein isoforms have been described and the possibility of functio nal differences between various isoforms has been raised. Previously, we demonstrated significant MDM-2 mRNA overexpression in human leukemi as and suggested that MDM-2 overexpression may be a marker of aggressi veness of the disease. Polyclonal antibodies (Ab) have been generated to detect various isoforms of the MDM-2 protein. Using these Abs, we c onfirmed MDM-2 protein overexpression in leukemias. Furthermore, we ob served heterogeneity in the isoforms expressed in various types of leu kemias. In addition, we demonstrated that analysis by flow cytometry c ould be used as a diagnostic tool for detecting altered MDM-2 protein expression in leukemias. Here we review and expand our initial observa tions and confirm MDM-2 mRNA and protein overexpression by reverse tra nscription-polymerase chain reaction (RT-PCR), flow cytometry, and wes tern blot analyses. Understanding the possible role of MDM-2 oncogene expression in leukemias may establish the scientific basis for new the rapeutic approaches.