An emerging concept in the field of cancer biology is that a rare population of ‘tumour stem cells’ exists among the heterogeneous group of cells that constitute a tumour. This concept, best described with human leukaemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Here we show that the Polycomb group gene Bmi-1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia. Complementation studies showed that Bmi-1 completely rescues these proliferative defects. These studies therefore indicate that Bmi-1 has an essential role in regulating the proliferative activity of both normal and leukaemic stem cells.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997)
Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994)
Appelbaum, F. R., Rowe, J. M., Radich, J. & Dick, J. E. Acute myeloid leukemia. Hematology (Am. Soc. Hematol. Educ. Program), 62–86 (2001)
Jordan, C. T. et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000)
Testa, U. et al. Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood 100, 2980–2988 (2002)
Lessard, J., Baban, S. & Sauvageau, G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 91, 1216–1224 (1998)
Lessard, J. et al. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999)
Park, I. K. et al. Differential gene expression profiling of adult murine hematopoietic stem cells. Blood 99, 488–498 (2002)
van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–759 (1994)
Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998)
Borrow, J. et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nature Genet. 12, 159–167 (1996)
Nakamura, T. et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nature Genet. 12, 154–158 (1996)
Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999)
Weber, H. O., Samuel, T., Rauch, P. & Funk, J. O. Human p14(ARF)-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 21, 3207–3212 (2002)
Kamijo, T. et al. Functional and physical interactions of the ARF tumour suppressor with p53 and Mdm2. Proc. Natl Acad. Sci. USA 95, 8292–8297 (1998)
Porcher, C. et al. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47–57 (1996)
Sauvageau, G. et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 9, 1753–1765 (1995)
Vonlanthen, S. et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br. J. Cancer 84, 1372–1376 (2001)
Dimri, G. P. et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 62, 4736–4745 (2002)
Thorsteinsdottir, U. et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 99, 121–129 (2002)
Sauvageau, G. et al. Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 6, 13–22 (1997)
Krosl, J. et al. Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1. Oncogene 16, 3403–3412 (1998)
Brady, G., Barbara, M. & Iscove, N. N. Representative in vitro cDNA amplification from individual hemopoietic cells and colonies. Mol. Cell. Biol. 2, 17–25 (1990)
Park, I.-K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic cells. Nature advance online publication, 20 April 2003 (doi: 10.1038/nature01587)
We thank S. Niessen and M. F. Clarke and colleagues for critically reading the manuscript, J. Hébert and P. Lussier for specimens and cytogenetics, J. Krosl, S. Girard and N. Mayotte for technical assistance, M.-E. Leroux and S. Matte for their expertise and help regarding the maintenance and manipulation of the animals kept at the SPF facility, N. Tessier and E. Massicotte for studies with the flow cytometer, C. Charbonneau for the imaging service of IRCM, and M. van Lohuizen and R. G. Hawley for the Bmi-1-/- mice and the MSCV vector, respectively. This work was supported by a grant from the Canadian Institute of Health Research (CIHR). J.L. was a recipient of a studentship from the CIHR and G.S. is a Scholar from the Leukemia and Lymphoma Society of America.
The authors declare that they have no competing financial interests.
About this article
Cite this article
Lessard, J., Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003). https://doi.org/10.1038/nature01572
Cell Death & Disease (2021)
Scientific Reports (2021)
Nature Reviews Molecular Cell Biology (2021)
Stem Cell Reviews and Reports (2021)
Nature Chemical Biology (2021)