TY - JOUR
T1 - PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2
AU - Aikawa, Yukiko
AU - Katsumoto, Takuo
AU - Zhang, Pu
AU - Shima, Haruko
AU - Shino, Mika
AU - Terui, Kiminori
AU - Ito, Etsuro
AU - Ohno, Hiroaki
AU - Stanley, E. Richard
AU - Singh, Harinder
AU - Tenen, Daniel G.
AU - Kitabayashi, Issay
N1 - Funding Information:
We would like to thank D.E. Zhang for the CSF1R promoter mutant lacking PU.1-binding sites, Y. Kamei and A. Iwama for MOZ-TIF2 cDNA, H. Ichikawa for N-MYC cDNA, T. Taya for SaOS2 cells (National Cancer Center Research Institute) and A. Kuchiba for help with statistical analyses. This work was supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare and from the Japanese Ministry of Education, Culture, Sports, Science and Technology (I.K.), by the Program for Promotion of Fundamental Studies from the National Institute of Biomedical Innovation of Japan (I.K.), and by US National Institutes of Health grants R01-CA41456 (D.G.T.), CA32551 and 5P30-CA13330 (E.R.S.).
PY - 2010/5
Y1 - 2010/5
N2 - Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by 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 MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R high cells), but not those expressing low amounts of CSF1R (CSF1R low cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R high cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R high cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.
AB - Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by 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 MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R high cells), but not those expressing low amounts of CSF1R (CSF1R low cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R high cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R high cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.
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U2 - 10.1038/nm.2122
DO - 10.1038/nm.2122
M3 - Article
C2 - 20418886
AN - SCOPUS:77952238153
SN - 1078-8956
VL - 16
SP - 580
EP - 585
JO - Nature Medicine
JF - Nature Medicine
IS - 5
ER -
