THE BIOLOGIC FUNCTION OF PML AND ITS ROLE IN ACUTE PROMYELOCYTIC LEUKEMIA

Patients with acute promyelocytic leukemia (APL) are characterized by the presence of a t(15;17) chromosomal translocation. The fusion prote in PML-RAR alpha encoded from the breakpoint can form a heterodimer an d acts as a dominant negative inhibitor against the normal function of PML. Recently we demonstrated that PML is a growth suppressor and tra nscription suppressor expressed in all cell lines tested. We also foun d that PML suppresses the clonogenicity and tumorigenicity of APL-deri ved NB4 cells, as well as the transformation of rat embryo fibroblasts by cooperative oncogenes and NIH/3T3 by neu. Overexpression of PML in human tumor cell lines induces a remarkable reduction in growth rate in vitro and in vivo. More recently, we have shown that PML is a phosp hoprotein associated with the nuclear matrix and that its expression i s cell cycle related. PML expression is altered during human oncogenes is, implying that PML may be an anti-oncogene involved not only in APL but also in other oncogenic events, Mutation analysis of the function al domains of PML demonstrated that its ability to form PML nuclear bo dies or PODs (PML oncogenic domains) is essential for suppressing grow th and transformation. In light of the above studies it appears that d isruption of the normal function of PML plays a critical role in the p athogenesis of APL.