title: Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells.
abstract: 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.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, 1280 Main Street West, Hamilton, ON, Canada L8S 4K1.
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Branavan
authors.initials: B
authors.lastname: Manoranjan
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Gunnarsson
authors.forename: Robert
authors.initials: R
authors.lastname: Hollenberg
authors.forename: Paula
authors.initials: P
authors.lastname: Klurfan
authors.forename: Naresh
authors.initials: N
authors.lastname: Murty
authors.forename: Jacek
authors.initials: J
authors.lastname: Kwiecien
authors.forename: Forough
authors.initials: F
authors.lastname: Farrokhyar
authors.forename: John P
authors.initials: JP
authors.lastname: Provias
authors.forename: Christopher
authors.initials: C
authors.lastname: Wynder
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002469:Cell Separation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C069077:BMI1 protein, human; D006023:Glycoproteins; D009687:Nuclear Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1