PU.1-Mediated Upregulation of M-CSFR Is Critical for MOZ-Leukemia Stem Cell Potential.

Abstract 216

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. The eradication of cancer stem cells is thought to be critical for successful anti-cancer therapy. However, there is little evidence for this. Using an acute myeloid leukemia (AML) model 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. Chromosomal translocations that involve the MOZ gene are typically associated with the FAB-M4 or -M5 subtype of human AML and often predict a poor prognosis. While MOZ is essential for the self-renewal of hematopoietic stem cells, MOZ-fusion proteins enable the transformation of non–self-renewing myeloid progenitors into leukemia stem cells. The MOZ-fusion proteins interacted with PU.1 to stimulate the expression of macrophage-colony stimulating factor receptor (M-CSFR). Cells expressing high levels of M-CSFR (M-CSFR -high cells), but not those expressing low levels of M-CSFR, showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the M-CSFR promoter, AML was cured by ablation of the M-CSFR -high cells. Analysis of M-CSFR-deficient and PU.1-deficient mice showed that M-CSFR and PU.1 was essential to induce AML. Inhibitors for tyrosine kinases including M-CSFR slowed the progress of MOZ-TIF2-induced leukemia. Thus, M-CSFR -high cells contain leukemia stem cells, and the PU.1-mediated upregulation of M-CSFR is a useful therapeutic target for MOZ leukemia.