title: BCL-XL mediates the strong selective advantage of a 20q11.21 amplification commonly found in human embryonic stem cell cultures.
abstract: Human embryonic stem cells (hESCs) regularly acquire nonrandom genomic aberrations during culture, raising concerns about their safe therapeutic application. The International Stem Cell Initiative identified a copy number variant (CNV) amplification of chromosome 20q11.21 in 25% of hESC lines displaying a normal karyotype. By comparing four cell lines paired for the presence or absence of this CNV, we show that those containing this amplicon have higher population doubling rates, attributable to enhanced cell survival through resistance to apoptosis. Of the three genes encoded within the minimal amplicon and expressed in hESCs, only overexpression of BCL2L1 (BCL-XL isoform) provides control cells with growth characteristics similar to those of CNV-containing cells, whereas inhibition of BCL-XL suppresses the growth advantage of CNV cells, establishing BCL2L1 as a driver mutation. Amplification of the 20q11.21 region is also detectable in human embryonal carcinoma cell lines and some teratocarcinomas, linking this mutation with malignant transformation.
authors.affiliation: Institute of Medical Biology, A-STAR, Immunos, Singapore 138648.
authors.forename: Stuart
authors.initials: S
authors.lastname: Avery
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Hirst
authors.forename: Duncan
authors.initials: D
authors.lastname: Baker
authors.forename: Chin Yan
authors.initials: CY
authors.lastname: Lim
authors.forename: Sharmini
authors.initials: S
authors.lastname: Alagaratnam
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Martin F
authors.initials: MF
authors.lastname: Pera
authors.forename: Alan
authors.initials: A
authors.lastname: Colman
authors.forename: Paul
authors.initials: P
authors.lastname: Robson
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrews
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Knowles
mesh_terms: D002460:Cell Line; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D056915:DNA Copy Number Variations; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005784:Gene Amplification; D056426:Genetic Loci; D006801:Humans; D009154:Mutation; D012641:Selection, Genetic; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051020:bcl-X Protein