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PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model
Louise M Kelly1, Jeffrey L Kutok, Ifor R Williams
1Division of Hematology/Oncology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor alpha (RARalpha). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RARalpha in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML/RARalpha from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML/RARalpha can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML/RARalpha transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML/RARalpha transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML/RARalpha and FLT3-ITD in development of the murine APL phenotype.
Insights
This study demonstrates that the PML/RARalpha fusion protein cooperates with FLT3-ITD mutations to accelerate the development of acute promyelocytic leukemia (APL)-like disease in mice, offering insights into APL pathogenesis.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Acute promyelocytic leukemia (APL) is characterized by PML/RARalpha fusion proteins.
- Additional mutations, such as in FLT3, are implicated in APL development.
- FLT3-ITD mutations alone cause myeloproliferative disease but not AML.
Purpose of the Study:
- To investigate the cooperative effect of PML/RARalpha and FLT3-ITD in inducing APL-like disease in mice.
- To determine if FLT3-ITD can substitute for secondary mutations in APL development.
Main Methods:
- Expression of PML/RARalpha in transgenic mice.
- Retroviral transduction of FLT3-ITD into bone marrow cells from PML/RARalpha transgenic mice.
- Assessment of disease latency, penetrance, and transplantability.
Main Results:
- Co-expression of PML/RARalpha and FLT3-ITD resulted in short-latency APL-like disease with complete penetrance.
- The induced leukemia was transplantable and responsive to ATRA treatment.
- FLT3-ITD mutations functionally substituted for secondary mutations in APL progression.
Conclusions:
- PML/RARalpha and FLT3-ITD cooperate to induce a rapid APL-like phenotype in mice.
- Activating FLT3 mutations can accelerate APL development, mimicking the role of additional mutations.
- This model provides a platform for studying APL pathogenesis and therapeutic strategies.