DNA methyltransferase 3A (DNMT3A) is mutated in hematologic malignancies affecting myeloid, mixed, and lymphoid lineages, and these mutations are associated with poor prognosis. Past studies in mice revealed Dnmt3a-knockout (KO)hematopoietic stem cells (HSCs) had increased self-renewal, but no leukemia was observed. Here, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 year. Animals were diagnosed with a spectrum of malignancies similar to those seen in patients with DNMT3A mutations, including myelodysplastic syndrome, acute myeloid leukemia, primary myelofibrosis, and T- and B-cell acute lymphocytic leukemia. In some cases, acquired malignancies exhibited secondary mutations similar to those identified in patients. Loss of Dnmt3a led to disturbed methylation patterns that were distinct in lymphoid and myeloid disease, suggesting lineage-specific methylation aberrations promoted by Dnmt3a loss. Global hypomethylation was observed in all of the malignancies, but lymphoid malignancies also exhibited hypermethylation, particularly at promoter regions. This mouse model underscores the important role of Dnmt3a in normal hematopoietic development and demonstrates that Dnmt3a loss of function confers a preleukemic phenotype on murine HSCs. This model may serve as a tool to study DNMT3A mutation associated malignancies and for developing targeted strategies for eliminating preleukemic cells for prevention and treatment of hematologic malignancies in the future.