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 protein PML-RAR alpha encoded from the breakpoint can form a heterodimer and acts as a dominant negative inhibitor against the normal function of PML. Recently we demonstrated that PML is a growth suppressor and transcription suppressor expressed in all cell lines tested. We also found that PML suppresses the clonogenicity and tumorigenicity of APL-derived 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 phosphoprotein associated with the nuclear matrix and that its expression is cell cycle related. PML expression is altered during human oncogenesis, implying that PML may be an anti-oncogene involved not only in APL but also in other oncogenic events. Mutation analysis of the functional domains of PML demonstrated that its ability to form PML nuclear bodies or PODs (PML oncogenic domains) is essential for suppressing growth and transformation. In light of the above studies it appears that disruption of the normal function of PML plays a critical role in the pathogenesis of APL.
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Division of Laboratory Medicine, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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Glassman
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Chang
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D000818:Animals; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human