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Pml is essential for multiple apoptotic pathways

Abstract

The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage–induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor α (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml –/– mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RARα fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.

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Figure 1: Pml–/– mice and cells are resistant to γ-irradiation–induced apoptosis.
Figure 2: Pml is required for DNA-damage–induced apoptosis in ConA-activated splenocytes.
Figure 3: Pml inactivation protects mice and cells from Fas-induced apoptosis.
Figure 4: Reduced caspase activation in Pml–/– splenocytes upon γ-irradiation.
Figure 5: Pml–/– cells are resistant to C2-ceramide–induced apoptosis.
Figure 6: Pml is essential for Fas-, TNF- and IFN-induced apoptosis of haemopoietic cells.
Figure 7: PML-RARα renders haemopoietic progenitors resistant to TNF-, Fas- and IFN-induced apoptosis.

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Acknowledgements

We thank M. Barna, M. Giorgio, E. Rego, K. Elkon, C. Cordon-Cardo, R. Dalla Favera, H.T. Petrie, S. Landolfo, P. Freemont, L. Longo and L. Luzzatto for materials, advice and help. Partially supported by the 'American Italian Cancer Foundation' (D.R.), the 'Associazione Italiana per la Ricerca sul Cancro' (M.G., R.R.) and 'Centro Nazionale per la Ricerca' (S.R.). P.P.P. is a Scholar of the Leukemia Society of America. Supported by the Sloan-Kettering Institute (CA-08748) and NIH (CA 71692 awarded to P.P.P.).

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Correspondence to Pier Paolo Pandolfi.

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Wang, ZG., Ruggero, D., Ronchetti, S. et al. Pml is essential for multiple apoptotic pathways. Nat Genet 20, 266–272 (1998). https://doi.org/10.1038/3073

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