Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2

Nature Medicine volume 16, pages 580–585 (2010)Cite this article

Subjects

Abstract

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer1,2. 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 (CSF1Rhigh cells), but not those expressing low amounts of CSF1R (CSF1Rlow 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 CSF1Rhigh 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 CSF1Rhigh cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CSF1Rhigh cells show potent leukemia-initiating activity.
Figure 2: Cure of AML by ablation of CSF1Rhigh cells.
Figure 3: The requirement for CSF1R in MOZ-TIF2–induced AML.
Figure 4: PU.1-dependent upregulation of CSF1R by MOZ-fusion proteins.

Similar content being viewed by others

References

  1. Bonnet, D. & Dick, J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article  CAS  Google Scholar 

  2. Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  Google Scholar 

  3. Borrow, J. et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat. Genet. 14, 33–41 (1996).

    Article  CAS  Google Scholar 

  4. Katsumoto, T., Yoshida, N. & Kitabayashi, I. Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. Cancer Sci. 99, 1523–1527 (2008).

    Article  CAS  Google Scholar 

  5. Katsumoto, T. et al. MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 20, 1321–1330 (2006).

    Article  CAS  Google Scholar 

  6. Thomas, T. et al. Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 20, 1175–1186 (2006).

    Article  CAS  Google Scholar 

  7. Huntly, B.J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).

    Article  CAS  Google Scholar 

  8. Deguchi, K. et al. MOZ-TIF2–induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell 3, 259–271 (2003).

    Article  CAS  Google Scholar 

  9. Terui, K. et al. Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). Haematologica 93, 1591–1593 (2008).

    Article  CAS  Google Scholar 

  10. Burnett, S.H. et al. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J. Leukoc. Biol. 75, 612–623 (2004).

    Article  CAS  Google Scholar 

  11. Kawagoe, H., Kandilci, A., Kranenburg, T.A. & Grosveld, G.C. Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice. Cancer Res. 67, 10677–10685 (2007).

    Article  CAS  Google Scholar 

  12. Dai, X.M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies and reproductive defects. Blood 99, 111–120 (2002).

    Article  CAS  Google Scholar 

  13. Ohno, H. et al. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol. Cancer Ther. 5, 2634–2643 (2006).

    Article  CAS  Google Scholar 

  14. Taylor, J.R., Brownlow, N., Domin, J. & Dibb, N.J. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene 25, 147–151 (2006).

    Article  CAS  Google Scholar 

  15. Dewar, A.L., Zannettino, A.C., Hughes, T.P. & Lyons, A.B. Inhibition of c-fms by imatinib: expanding the spectrum of treatment. Cell Cycle 4, 851–853 (2005).

    Article  CAS  Google Scholar 

  16. Dewar, A.L. et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 105, 3127–3132 (2005).

    Article  CAS  Google Scholar 

  17. Zhang, D.E. et al. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol. Cell. Biol. 16, 1231–1240 (1996).

    Article  CAS  Google Scholar 

  18. Kitabayashi, I., Aikawa, Y., Nguyen, L.A., Yokoyama, A. & Ohki, M. Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J. 20, 7184–7196 (2001).

    Article  CAS  Google Scholar 

  19. Hoogenkamp, M. et al. Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. Blood 114, 299–309 (2009).

    Article  CAS  Google Scholar 

  20. Walsh, J.C. et al. Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. Immunity 17, 665–676 (2002).

    Article  CAS  Google Scholar 

  21. Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998).

    Article  CAS  Google Scholar 

  22. Jin, G. et al. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 109, 3998–4005 (2007).

    Article  CAS  Google Scholar 

  23. Wang, C. et al. Expression of the CSF-1 gene in the blast cells of acute myeloblastic leukemia: association with reduced growth capacity. J. Cell. Physiol. 135, 133–138 (1988).

    Article  CAS  Google Scholar 

  24. Rambaldi, A. et al. Expression of the macrophage colony–stimulating factor and c-fms genes in human acute myeloblastic leukemia cells. J. Clin. Invest. 81, 1030–1035 (1988).

    Article  CAS  Google Scholar 

  25. Preisler, H.D., Kinniburgh, A.J., Wei-Dong, G. & Khan, S. Expression of the protooncogenes c-myc, c-fos and c-fms in acute myelocytic leukemia at diagnosis and in remission. Cancer Res. 47, 874–880 (1987).

    CAS  PubMed  Google Scholar 

  26. Gisselbrecht, S. et al. Frequent c-fms activation by proviral insertion in mouse myeloblastic leukaemias. Nature 329, 259–261 (1987).

    Article  CAS  Google Scholar 

  27. Heard, J.M., Roussel, M.F., Rettenmier, C.W. & Sherr, C.J. Multilineage hematopoietic disorders induced by transplantation of bone marrow cells expressing the v-fms oncogene. Cell 51, 663–673 (1987).

    Article  CAS  Google Scholar 

  28. Gu, T.L. et al. A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia. Blood 110, 323–333 (2007).

    Article  CAS  Google Scholar 

  29. Iwasaki, H. et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106, 1590–1600 (2005).

    Article  CAS  Google Scholar 

  30. Seibler, J. et al. Rapid generation of inducible mouse mutants. Nucleic Acids Res. 31, e12 (2003).

    Article  Google Scholar 

  31. Morita, S., Kojima, T. & Kitamura, T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063–1066 (2000).

    Article  CAS  Google Scholar 

  32. Zhang, D.E., Hetherington, C.J., Chen, H.M. & Tenen, D.G. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol. Cell. Biol. 14, 373–381 (1994).

    Article  CAS  Google Scholar 

  33. Yoshida, H. et al. PML-retinoic acid receptor α inhibits PML IV enhancement of PU.1-induced C/EBPɛ expression in myeloid differentiation. Mol. Cell. Biol. 27, 5819–5834 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.).

Author information

Authors and Affiliations

  1. Molecular Oncology Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.,

    Yukiko Aikawa, Takuo Katsumoto, Haruko Shima, Mika Shino & Issay Kitabayashi

  2. Harvard Stem Cell Institute, Boston, Massachusetts, USA

    Pu Zhang & Daniel G Tenen

  3. Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan

    Kiminori Terui & Etsuro Ito

  4. Research Division, Pharmacological Research Laboratories, Kyowa Hakko Kirin, Gunma, Japan.,

    Hiroaki Ohno

  5. Albert Einstein College of Medicine, Bronx, New York, USA

    E Richard Stanley

  6. Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA

    Harinder Singh

  7. Cancer Science Institute, National University of Singapore, Singapore

    Daniel G Tenen

Authors
  1. Yukiko Aikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takuo Katsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruko Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mika Shino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kiminori Terui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Etsuro Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroaki Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Richard Stanley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Harinder Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel G Tenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Issay Kitabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.A., I.K., T.K. and M.S. conducted experiments in AML mice. Y.A., H. Shima and I.K. performed western blotting, immunoprecipitation, GST pull down, ChIP and reporter assays. P.Z. and D.G.T. conducted experiments in PU.1-deficient mice. E.R.S. designed and performed experiments in CSF1R-deficient mice. K.T. and E.I. analyzed expression of CSF1R in human AML cells. H. Singh designed and performed experiments in PUER cells. H.O. prepared Ki20227. I.K. and Y.A. analyzed data and edited the manuscript.

Corresponding author

Correspondence to Issay Kitabayashi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 (PDF 3848 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aikawa, Y., Katsumoto, T., Zhang, P. et al. PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. Nat Med 16, 580–585 (2010). https://doi.org/10.1038/nm.2122

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2122

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer