Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells

Chitra Venugopal, Na Li, Xin Wang, Branavan Manoranjan, Cynthia Hawkins, Thorsteinn Gunnarsson, Robert Hollenberg, Paula Klurfan, Naresh Murty, Jacek Kwiecien, Forough Farrokhyar, John P Provias, Christopher Wynder, Sheila K Singh
Stem Cell Research 2012, 8 (2): 141-53
The master regulatory gene Bmi1 modulates key stem cell properties in neural precursor cells (NPCs), and has been implicated in brain tumorigenesis. We previously identified a population of CD133+ brain tumor cells possessing stem cell properties, known as brain tumor initiating cells (BTICs). Here, we characterize the expression and role of Bmi1 in primary minimally cultured human glioblastoma (GBM) patient isolates in CD133+ and CD133- sorted populations. We find that Bmi1 expression is increased in CD133- cells, and Bmi1 protein and transcript expression are highest during intermediate stages of differentiation as CD133+ BTICs lose their CD133 expression. Furthermore, in vitro stem cell assays and Bmi1 knockdown show that Bmi1 contributes to self-renewal in CD133+ populations, but regulates proliferation and cell fate determination in CD133- populations. Finally, we test if our in vitro stem cell assays and Bmi1 expression in BTIC patient isolates are predictive of clinical outcome for GBM patients. Bmi1 expression profiles show a marked elevation in the proneural GBM subtype, and stem cell frequency as assessed by tumor sphere assays correlates with patient outcome.

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