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A PMLRARalpha transgene initiates murine acute promyelocytic leukemia
1G.W. Hooper Foundation, Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0552, USA.
Abstract:
The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
Insights
Transgenic mice expressing the PMLRAR alpha fusion gene developed acute promyelocytic leukemia (APL), demonstrating its role in initiating the disease. This model accurately mimics human APL and its response to retinoic acid therapy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translocation.
- This translocation fuses the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RAR alpha) gene, creating the PMLRAR alpha fusion protein.
Purpose of the Study:
- To investigate the role of the PMLRAR alpha chimera in leukemogenesis.
- To establish a mouse model for studying APL development and treatment.
Main Methods:
- Expression of a PMLRAR alpha cDNA in myeloid cells of transgenic mice.
- Transplantation of preleukemic and leukemic cells to nontransgenic mice.
- Assessment of disease progression and response to retinoic acid.
Main Results:
- PMLRAR alpha transgenic mice showed impaired neutrophil maturation and developed APL.
- The induced APL recapitulated key features of human APL, including differentiation in response to retinoic acid.
- Retinoic acid treatment induced remission in both preleukemic and APL states in mice.
Conclusions:
- The PMLRAR alpha fusion protein is crucial for initiating APL by impairing neutrophil differentiation.
- The developed transgenic mouse model accurately reflects human APL and its therapeutic response.
- This model is valuable for exploring APL pathogenesis and preclinical therapeutic studies.