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Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells

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Abstract

Purpose

Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs.

Methods

Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1.

Results

There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties.

Conclusions

Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.

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Authors and Affiliations

  1. Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Parvez Vora, Mathieu Seyfrid, Chitra Venugopal, Maleeha A. Qazi, Minomi Subapanditha, Erin O’Farrell, Sujeivan Mahendram, David Bakhshinyan, Chirayu Chokshi, Nicole McFarlane & Sheila K. Singh

  2. Department of Surgery, McMaster University, Hamilton, ON, Canada

    Parvez Vora, Mathieu Seyfrid, Chitra Venugopal, Sujeivan Mahendram, Nicole McFarlane, Naresh Murty & Sheila K. Singh

  3. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    Maleeha A. Qazi, Sabra Salim, Erin O’Farrell, Mohini Singh, David Bakhshinyan, Chirayu Chokshi & Sheila K. Singh

  4. Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Ruth Isserlin, Kevin R. Brown, Jason Moffat & Gary D. Bader

  5. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Anna Dvorkin-Gheva

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  1. Parvez Vora
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Vora, P., Seyfrid, M., Venugopal, C. et al. Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells. J Neurooncol 143, 417–428 (2019). https://doi.org/10.1007/s11060-019-03192-1

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