Abstract
The PML-RARα hybrid protein generated by the t(15;17) translocation in acute promyelocytic leukemia (APL) is thought to play a central role in the oncogenic process. However, analysis of the oncogenic activity of the fusion protein in tissue culture assays or in mice has been hampered by its apparent toxicity in multiple murine cells. To circumvent this problem, we generated an inducible line of transgenic mice, MT135, in which the expression of PML-RARα is driven by the metallothionein promoter. After 5 days zinc stimulation, 27 out of 54 mice developed hepatic preneoplasia and neoplasia including foci of basophilic hepatocytes, dysplasia and carcinoma with a significantly higher incidence of lesions in females than in males. The rapid onset of liver pathologies was dependent on overexpression of the transgene since it was not detected in noninduced transgenic animals of the same age. The PML-RARα protein was always present in altered tissues at much higher levels than in the surrounding normal liver tissues. In addition, overexpression of PML-RARα resulted in a strong proliferative response in the hepatocytes. We conclude that overexpression of PML-RARα deregulates cell proliferation and can induce tumorigenic changes in vivo.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
David, G., Terris, B., Marchio, A. et al. The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice. Oncogene 14, 1547–1554 (1997). https://doi.org/10.1038/sj.onc.1200989
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1200989
Keywords
This article is cited by
-
Acute promyelocytic leukaemia: population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021
BMC Cancer (2023)
-
How patients have benefited from mouse models of acute promyelocytic leukaemia
Nature Reviews Cancer (2005)
-
Acute promyelocytic leukemia: PML/RARα and the leukemic stem cell
Leukemia (2004)
-
Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARα
Oncogene (2004)
-
Taking apart a cancer protein
Nature (2003)