1. The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia
- Author
-
Bo T. Porse, Anne Wenzel, Adrija Kalvisa, Anna S. Wilhelmson, Sachin Pundhir, Anne Meldgaard Hansen, Mikkel Bruhn Schuster, and Teresa D'Altri
- Subjects
Myeloid ,Context (language use) ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,CEBPA ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Mutation ,Myeloproliferative Disorders ,business.industry ,Myeloid leukemia ,Hematology ,medicine.disease ,Hematopoiesis ,Repressor Proteins ,Transplantation ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,business - Abstract
ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.
- Published
- 2020