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Published on: January 6, 2023
Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha
Mahadeo A Sukhai1, Xuemei Wu, Yali Xuan
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Acute promyelocytic leukemia (APL) is characterized by the accumulation of abnormal promyelocytes in the bone marrow (BM), and by the presence of a reciprocal chromosomal translocation involving retinoic acid receptor alpha (RARalpha). To date, five RARalpha partner genes have been identified in APL. NuMA-RARalpha was identified in a pediatric case of APL carrying a translocation t(11;17)(q13;q21). Using a construct containing the NuMA-RARalpha fusion gene driven by the human cathepsin G promoter (hCG-NuMA-RARalpha), two transgenic mouse lines were generated. Transgenic mice were observed to have a genetic myeloproliferation (increased granulopoiesis in BM) at an early age, and rapidly developed a myeloproliferative disease-like myeloid leukemia. This leukemia was morphologically and immunophenotypically indistinguishable from human APL, with a penetrance of 100%. The phenotype of transgenic mice was consistent with a blockade of neutrophil differentiation. NuMA-RARalpha is therefore sufficient for disease development in this APL model.
Insights
A novel fusion gene, NuMA-RARalpha, drives myeloid leukemia in mice, mimicking human acute promyelocytic leukemia (APL). This discovery highlights the gene
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia.
- APL is characterized by abnormal promyelocyte accumulation in bone marrow.
- A key feature of APL is a chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) gene.
Purpose of the Study:
- To investigate the role of the NuMA-RARalpha fusion gene in APL development.
- To establish a mouse model for studying APL pathogenesis.
Main Methods:
- Generated transgenic mouse lines using a construct with the NuMA-RARalpha fusion gene driven by the human cathepsin G promoter (hCG-NuMA-RARalpha).
- Observed transgenic mice for hematological and morphological changes.
- Evaluated leukemia phenotype for similarity to human APL.
Main Results:
- Transgenic mice exhibited genetic myeloproliferation (increased granulopoiesis) and rapidly developed myeloid leukemia.
- The induced leukemia was morphologically and immunophenotypically indistinguishable from human APL.
- Disease penetrance in transgenic mice was 100%.
Conclusions:
- The NuMA-RARalpha fusion gene is sufficient for the development of APL.
- The transgenic mouse model accurately recapitulates human APL, including blocked neutrophil differentiation.
- This model provides a valuable tool for APL research.
