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Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation
S C Kogan1, S H Hong, D B Shultz
1G.W. Hooper Foundation and Department of Laboratory Medicine, University of California, San Francisco, CA 94143-0100, USA.
Abstract:
The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRARalpha and RARalphaPML fusion genes. We previously developed a mouse model of APL by expressing PMLRARalpha in murine myeloid cells. In order to examine the mechanisms by which PMLRARalpha can initiate leukemia, we have now generated transgenic mice expressing PMLRARalpham4 and RARalpham4, proteins that are unable to activate transcription in response to retinoic acid. PMLRARalpham4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRARalpha is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARalpham4 transgenic mice varied from those previously observed in our PMLRARalpha transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARalpham4 transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through the PMLRARalpha protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARalpham4 have not developed leukemia, providing evidence that the PML domain of PMLRARalpha plays a specific and critical role in the pathogenesis of APL. (Blood. 2000;95:1541-1550)
Insights
Transcriptional activation by PML-RARalpha is not required for acute promyelocytic leukemia (APL) development. However, ligand responsiveness influences leukemic cell phenotype and retinoic acid therapy effectiveness in APL.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Acute promyelocytic leukemia (APL) is characterized by the t(15;17) chromosomal translocation, forming PML-RARalpha fusion genes.
- Previous studies established a mouse model for APL using PML-RARalpha expression in myeloid cells.
Purpose of the Study:
- To investigate the mechanisms of leukemic transformation by PML-RARalpha.
- To determine if transcriptional activation by PML-RARalpha is essential for initiating leukemia.
- To explore the role of ligand responsiveness in APL pathogenesis and therapy.
Main Methods:
- Generated transgenic mice expressing PML-RARalpha variants (PMLRARalpham4 and RARalpham4) that are unresponsive to retinoic acid.
- Analyzed leukemic transformation and characteristics in these mouse models.
- Assessed the response to retinoic acid therapy in leukemic cells.
Main Results:
- PMLRARalpham4 transgenic mice developed myeloid leukemia, proving transcriptional activation is not required for transformation.
- Leukemias in PMLRARalpham4 mice exhibited varied characteristics compared to PML-RARalpha mice, suggesting ligand responsiveness impacts phenotype.
- Leukemias resistant to retinoic acid differentiation showed variable survival benefits, indicating potential therapeutic effects beyond direct differentiation.
- RARalpham4 transgenic mice did not develop leukemia, highlighting the critical role of the PML domain in APL pathogenesis.
Conclusions:
- Transcriptional activation by PML-RARalpha is dispensable for APL initiation.
- Ligand responsiveness of PML-RARalpha influences APL phenotype and response to retinoic acid therapy.
- The PML domain of PML-RARalpha is crucial for the development of APL.