PML, a growth suppressor disrupted in acute promyelocytic leukemia

Zhao Mei Mu, Khew Voon Chin, Jin Hwang Liu, Guillermina Lozano, Kun Sang Chang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

299 Scopus citations

Abstract

The nonrandom chromosomal translocation t(15;17)(q22;q21) in acute promyelocytic leukemia (APL) juxtaposes the genes for retinoic acid receptor α (RARα) and the putative zinc finger transcription factor PML. The breakpoint site encodes fusion protein PML-RARα, which is able to form a heterodimer with PML. It was hypothesized that PML-RARα is a dominant negative inhibitor of PML. Inactivation of PML function in APL may play a critical role in APL pathogenesis. Our results demonstrated that PML, but not PML-RARα, is a growth suppressor. This is supported by the following findings: (i) PML suppressed anchorage-independent growth of APL-derived NB4 cells on soft agar and tumorigenicity in nude mice, (ii) PML suppressed the oncogenic transformation of rat embryo fibroblasts by cooperative oncogenes, and (iii) PML suppressed transformation of NIH 3T3 cells by the activated neu oncogene. Cotransfection of PML with PML-RARα resulted in a significant reduction in PML's transformation suppressor function in vivo, indicating that the fusion protein can be a dominant negative inhibitor of PML function in APL cells. This observation was further supported by the finding that cotransfection of PML and PML-RARα resulted in altered normal cellular localization of PML. Our results also demonstrated that PML, but not PML- RARα, is a promoter-specific transcription suppressor. Therefore, we hypothesized that disruption of the PML gene, a growth or transformation suppressor, by the t(15;17) translocation in APL is one of the critical events in leukemogenesis.

Original languageEnglish
Pages (from-to)6858-6867
Number of pages10
JournalMolecular and Cellular Biology
Volume14
Issue number10
DOIs
StatePublished - Oct 1994

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