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HERO ID
2811518
Reference Type
Journal Article
Title
Role of promyelocytic leukemia (PML) protein in tumor suppression
Author(s)
Rego, EM; Wang, ZG; Peruzzi, D; He, LZ; Cordon-Cardo, C; Pandolfi, PP
Year
2001
Is Peer Reviewed?
Yes
Journal
Journal of Experimental Medicine
ISSN:
0022-1007
EISSN:
1540-9538
Volume
193
Issue
4
Page Numbers
521-529
Language
English
PMID
11181703
DOI
10.1084/jem.193.4.521
Web of Science Id
WOS:000167114900012
Abstract
The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor alpha (RARalpha) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARalpha oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML(-/-) mice with human cathepsin G (hCG)-PMLRARalpha or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARalpha TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARalpha TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARalpha are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
Keywords
promyelocytic leukemia protein; acute promyelocytic leukemia; leukemogenesis; apoptosis; transgenic mice
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