TY - JOUR AU - Teresa D'Altri, AU - Anna S. Wilhelmson, AU - Mikkel B. Schuster, AU - Anne Wenzel, AU - Adrija Kalvisa, AU - Sachin Pundhir, AU - Anne Meldgaard Hansen, AU - Bo T. Porse, PY - 2021/04/01 Y2 - 2024/03/29 TI - The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia JF - Haematologica JA - haematol VL - 106 IS - 4 SE - Articles DO - 10.3324/haematol.2019.235150 UR - https://haematologica.org/article/view/9741 SP - 1000-1007 AB - 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. ER -