Exome Sequencing of Dnmt3a-null Mouse Bone Marrow to Identify Co-Operating Mutations in Leukemic Transformation

Mice transplanted with Dnmt3a-null bone marrow in the absence of wild-type support cells succumb to bone marrow failure (median survival 328 days) characteristic of myelodysplastic syndromes (MDS) with symptoms including anemia, neutropenia, bone marrow hypercellularity and splenomegaly with myeloid infiltration. However, in about 10% of these mice the disease progresses to de novo acute myeloid leukemia (AML). We performed whole exome sequencing to identify co-operating genetic mutations that were specifically associated with leukemic transformation to AML in Dnmt3a-null bone marrow.