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.

  • Original Article
  • Published:

Oncogenes, Fusion Genes and Tumor Suppressor Genes

Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells

Leukemia volume 25, pages 1335–1343 (2011)Cite this article

Subjects

Abstract

The polycomb group (PcG) proteins, particularly Bmi1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, Bmi1−/− granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL–AF9. Although Bmi1 was not essential to the immortalization of GMPs in vitro, Bmi1−/− cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of Bmi1 including potential tumor suppressor genes. Transplantation assays demonstrated that Bmi1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of Bmi1−/− LSCs. Of note, the complementation of immortalized Bmi1−/−Ink4a-Arf−/− GMPs with Bmi1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that Bmi1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Pietersen AM, van Lohuizen M . Stem cell regulation by polycomb repressors: postponing commitment. Curr Opin Cell Biol 2008; 20: 201–207.

    Article  CAS  PubMed  Google Scholar 

  2. Lessard J, Sauvageau G . Bmi-1 determines proliferative capacity of normal and leukemic stem cells. Nature 2003; 423: 255–260.

    Article  CAS  PubMed  Google Scholar 

  3. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003; 423: 302–305.

    Article  CAS  PubMed  Google Scholar 

  4. Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product, Bmi-1. Immunity 2004; 21: 843–851.

    Article  CAS  PubMed  Google Scholar 

  5. Jacobs JJL, Kieboom K, Marino S, DePinho RA, van Lohuizen M . The oncogene and Polycomb-group gene bmi1 regulates proliferation and senescence through the ink4a locus. Nature 1999; 397: 164–168.

    Article  CAS  PubMed  Google Scholar 

  6. Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H . Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 2006; 203: 2247–2253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006; 125: 301–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Oguro H, Yuan J, Ichikawa H, Ikawa T, Yamazaki S, Kawamoto H et al. Poised lineage specification in multipotent hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell 2010; 6: 279–286.

    Article  CAS  PubMed  Google Scholar 

  9. Mihara K, Chowdhury M, Nakaju N, Hidani S, Ihara A, Hyodo H et al. Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood 2006; 107: 305–308.

    Article  CAS  PubMed  Google Scholar 

  10. Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV . The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007; 110: 380–383.

    Article  CAS  PubMed  Google Scholar 

  11. Chowdhury M, Mihara K, Yasunaga S, Ohtaki M, Takihara Y, Kimura A . Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia. Leukemia 2007; 21: 1116–1122.

    Article  CAS  PubMed  Google Scholar 

  12. Cozzio A, Passegu E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004; 6: 587–596.

    Article  CAS  PubMed  Google Scholar 

  14. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.

    Article  CAS  PubMed  Google Scholar 

  15. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008; 13: 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007; 39: 232–236.

    Article  CAS  PubMed  Google Scholar 

  17. Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T et al. Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol 2003; 31: 1007–1014.

    Article  CAS  PubMed  Google Scholar 

  18. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650–1652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Singh MK, Petry M, Haenig B, Lescher B, Leitges M, Kispert A . The T-box transcription factor Tbx15 is required for skeletal development. Mech Dev 2005; 122: 131–144.

    Article  CAS  PubMed  Google Scholar 

  20. Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008; 68: 7742–7749.

    Article  CAS  PubMed  Google Scholar 

  21. Rizo A, Olthof S, Han L, Vellenga E, de Haan G, Schuringa JJ . Repression of BMI1 in normal and leukemic human CD34+ cells impairs self-renewal and induces apoptosis. Blood 2009; 114: 1498–1505.

    Article  CAS  PubMed  Google Scholar 

  22. Bracken AP, Helin K . Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 2009; 9: 773–784.

    Article  CAS  PubMed  Google Scholar 

  23. Ortega S, Malumbres M, Barbacid M . Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochimica et Biophysica Acta 2002; 1602: 73–87.

    CAS  PubMed  Google Scholar 

  24. Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J et al. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007; 12: 328–341.

    Article  CAS  PubMed  Google Scholar 

  25. Wiederschain D, Chen L, Johnson B, Bettano K, Jackson D, Taraszka J et al. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Mol Cell Biol 2007; 27: 4968–4979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Douglas D, Hsu JH, Hung L, Cooper A, Abdueva D, van Doorninck J et al. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res 2008; 68: 6507–6515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Maarten van Lohuizen and Ronald A DePinho for providing Bmi1+/− mice and Ink4a+/− mice, respectively, and Lay Hess for the MLL-AF9 plasmid. This study was supported in part by Grants-in-aid for Scientific Research (#21390289) and for the Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), MEXT, Japan, a Grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Corporation (JST), and a grant from the Takeda Science Foundation.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan

    J Yuan, M Takeuchi, M Negishi, H Oguro & A Iwama

  2. Division of Hematology, Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan

    M Takeuchi

  3. Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    H Ichikawa

  4. JST, CREST, Chiyoda-ku, Tokyo, Japan

    J Yuan, M Negishi, H Oguro & A Iwama

Authors
  1. J Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Negishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Oguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Iwama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Iwama.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author Contributions

JY designed and conducted the research, performed experiments, interpreted the data, and wrote the paper; MT, MN and HO conducted research; HI performed the microarray analysis; and AI was responsible for execution of the research, interpretation of the data and the writing of the paper.

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, J., Takeuchi, M., Negishi, M. et al. Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells. Leukemia 25, 1335–1343 (2011). https://doi.org/10.1038/leu.2011.85

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.85

Keywords

This article is cited by

Search

Advanced search

Quick links