PU.1-mediated upregulation of M-CSFR is critical for MOZ-leukemia stem cell potential

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer 1 , 2 . Cancer stem cell eradication is thought to be critical for successful anti-cancer therapy. Using an acute myeloid leukemia (AML) model induced by introducing the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ-fusion proteins interacted with PU.1 to stimulate the expression of macrophage-colony stimulating factor receptor (M-CSFR, also called CSF1R/c-FMS/CD115). Analysis using PU.1-deficient mice demonstrated that PU.1 was essential for MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high levels of CSF1R (CSF1R high cells), but not those expressing low levels of CSF1R (CSF1R low/− cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, AML was cured by ablation of the CSF1R high cells. Induction of AML was suppressed in CSF1R-deficient mice. CSF1R inhibitors slowed the progress of MOZ-TIF2–induced leukemia. Thus, CSF1R high cells contain leukemia stem cells, and the PU.1-mediated upregulation of CSF1R may be a useful therapeutic target for MOZ leukemia.