The dynamic interactions between leukemic cells and cells resident within the bone marrow microenvironment are vital for leukemia progression. The lack of detailed knowledge about the cellular and molecular mechanisms involved in this cross-talk restricts the design of effective treatments. Guarnerio et al. (2018) by using state-of-the-art techniques, including sophisticated Cre/loxP technologies in combination with leukemia mouse models, reveal that mesenchymal stem cells via promyelocytic leukemia protein (Pml) maintain leukemic cells in the bone marrow niche. Strikingly, genetic deletion of Pml in mesenchymal stem cells raised survival of leukemic mice under chemotherapeutic treatment. The emerging knowledge from this research provides a novel target in the bone marrow niche for therapeutic benefit in leukemia.