Using a xenograft mouse model, we show that MTL-CEBPA upregulates CEBPA expression in AML cells when administered systemically and that this CEBPA upregulation results in the downstream upregulation of a C/EBPα-modulated gene, SPI1. We also show that CEPBA upregulation using MTL-CEBPA can enhance the anti-leukemic effects of gilteritinib and induce a greater reduction in leukemic burden than gilteritinib alone. Here, SPI1 is linked to acute myeloid leukemia.