Asxl1 and Cebpa cooperation in AML revealed by a novel Asxl1 mutant mouse model

Asxl1 is one of the most commonly mutated genes in malignancies including myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML). We generated a mouse model that harbors the most common mutation on ASXL1 gene detected in MDS patients: c.1934dupG, p.G646WfsX12 at the endogenous murine Asxl1 locus: the G643WfsX12 mutant, from here on referred as Asxl1G643W. Mutations on Asxl1 co-occur with mutations on CEBPA in AML patients, therefore, in order to understand how Asxl1 and Cebpa co-operate, we set up to cross our Cebpa-p30 mutant mouse model with our newly generated Asxl1 G643Wfs12 mutant. In this study we provided mechanistic information about the cooperation between these two factors. Furthermore, our mouse model proved able to recapitulate the chemotherapy response of human patients with Asxl1 mutations, thus representing a potent tool for future preclinical studies focusing on Asxl1 mutant AML. RNA sequencing of Cebpa-/p30; Asxl1WT and Cebpa-/p30; Asxl1G643W/G643W blast cells from transplanted mice