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Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells

Abstract

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.

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Figure 1: Bmi-1 regulates the proliferative potential of embryonic day (E)14.5 fetal liver (FL)-derived haematopoietic cells.
Figure 2: Bmi-1 is dispensable for the generation of AML in primary recipients.
Figure 3: Bmi-1 is essential for the ‘transplantability’ of AML into secondary hosts.
Figure 4: Characterization of control and Bmi-1-/- leukaemic cells in vitro.
Figure 5: Loss of expression of several CKIs in Bmi-1-/- Hoxa9Meis HPCs.
Figure 6: Bmi-1 rescues the weak leukaemogenic potential of Bmi-1-/- HPCs.

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Acknowledgements

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.

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Correspondence to Guy Sauvageau.

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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

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