PML, A GROWTH SUPPRESSOR DISRUPTED IN ACUTE PROMYELOCYTIC LEUKEMIA

Citation
Zm. Mu et al., PML, A GROWTH SUPPRESSOR DISRUPTED IN ACUTE PROMYELOCYTIC LEUKEMIA, Molecular and cellular biology, 14(10), 1994, pp. 6858-6867
Citations number
65
Categorie Soggetti
Biology
ISSN journal
02707306
Volume
14
Issue
10
Year of publication
1994
Pages
6858 - 6867
Database
ISI
SICI code
0270-7306(1994)14:10<6858:PAGSDI>2.0.ZU;2-P
Abstract
The nonrandom chromosomal translocation t(15;17)(q22;q21) in acute pro myelocytic leukemia (APL) juxtaposes the genes for retinoic acid recep tor alpha (RAR alpha) and the putative zinc finger transcription facto r PML. The breakpoint site encodes fusion protein PML-RAR alpha, which is able to form a heterodimer with PML. It was hypothesized that PML- RAR alpha is a dominant negative inhibitor of PML. Inactivation of PML function in APL may play a critical role in APL pathogenesis. Our res ults demonstrated that PML, but not PML-RAR alpha is a growth suppress or. This is supported by the following findings: (i) PML suppressed an chorage-independent growth of APL-derived NB4 cells on soft agar and t umorigenicity in nude mice, (ii) PML suppressed the oncogenic transfor mation of rat embryo fibroblasts by cooperative oncogenes, and (iii) P ML suppressed transformation of NIH 3T3 cells by the activated neu onc ogene. Cotransfection of PML with PML-RAR alpha resulted in a signific ant reduction in PML's transformation suppressor function in vivo, ind icating that the fusion protein can be a dominant negative inhibitor o f PML function in APL cells. This observation was further supported by the finding that cotransfection of PML and PML-RAR alpha resulted in altered normal cellular localization of PML. Our results also demonstr ated that PML, but not PML-RAR alpha, is a promoter-specific transcrip tion suppressor. Therefore, we hypothesized that disruption of the PML gene, a growth or transformation suppressor, by the t(15;17) transloc ation in APL is one of the critical events in leukemogenesis.