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

• Published in: Journal of neuro-oncology Vol. 143; no. 3; pp. 417 - 428
• Main Authors: Vora, Parvez, Seyfrid, Mathieu, Venugopal, Chitra, Qazi, Maleeha A., Salim, Sabra, Isserlin, Ruth, Subapanditha, Minomi, O’Farrell, Erin, Mahendram, Sujeivan, Singh, Mohini, Bakhshinyan, David, Chokshi, Chirayu, McFarlane, Nicole, Dvorkin-Gheva, Anna, Brown, Kevin R., Murty, Naresh, Moffat, Jason, Bader, Gary D., Singh, Sheila K.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2019; Springer Nature B.V
• Subjects: AC133 Antigen - genetics; AC133 Antigen - metabolism; Animals; Apoptosis; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cell Proliferation; Cell self-renewal; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Laboratory Investigation; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neural stem cells; Neurology; Oncology; Polycomb group proteins; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Population studies; Ribonucleic acid; RNA; Signal transduction; Stem cells; Survival; Transcription; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Patient-derived brain tumor initiating cells; BMI1; Glioblastoma; CD133
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-019-03192-1

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.