Impaired hematopoiesis and leukemia development in mice with a "knock-in" allele of U2af1(S34F)

We have generated mice that carry Cre-dependent "knock-in" alleles of U2af1(S34F), the murine version of a mutant allele commonly encountered in human myelodysplastic syndromes and acute myeloid leukemia (AML). Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development. Mice with Cre-dependent U2af1(S34F) and homozygous Runx1 "knockout" alleles were mutagenized with low-dose N-Ethyl-N-Nitrosourea, and three of fourteen mice developed AML. However, AML did not arise in mice with other genotypes in our relatively small cohort. Sequencing DNA from the three AMLs revealed somatic mutations considered to be drivers of human AML, including mutations in Tet2, Gata2, Idh1, and Ikzf1. However, the U2af1 missense mutation reverted to WT in two of the three AML cases, implying that U2af1(S34F) is dispensable for maintaining leukemia.