title: Cell of origin strongly influences genetic selection in a mouse model of T-ALL.
abstract: Identifying the normal cell from which a tumor originates is crucial to understanding the etiology of that cancer. However, retrospective identification of the cell of origin in cancer is challenging because of the accumulation of genetic and epigenetic changes in tumor cells. The biologic state of the cell of origin likely influences the genetic events that drive transformation. We directly tested this hypothesis by performing a Sleeping Beauty transposon mutagenesis screen in which common insertion sites were identified in tumors that were produced by mutagenesis of cells at varying time points throughout the T lineage. Mutation and gene expression data derived from these tumors were then compared with data obtained from a panel of 84 human T-cell acute lymphoblastic leukemia samples, including copy number alterations and gene expression profiles. This revealed that altering the cell of origin produces tumors that model distinct subtypes of human T-cell acute lymphoblastic leukemia, suggesting that even subtle changes in the cell of origin dramatically affect genetic selection in tumors. These findings have broad implications for the genetic analysis of human cancers as well as the production of mouse models of cancer.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Berquam-Vrieze
authors.forename: Kishore
authors.initials: K
authors.lastname: Nannapaneni
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Brett
authors.forename: Linda
authors.initials: L
authors.lastname: Holmfeldt
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Oksana
authors.initials: O
authors.lastname: Zagorodna
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
mesh_terms: D000818:Animals; D058948:Cell Tracking / Q000379:methods; D004195:Disease Models, Animal; D018628:Gene Dosage / Q000502:physiology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008954:Models, Biological; D016254:Mutagenesis, Insertional / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D012641:Selection, Genetic / Q000502:physiology*; D019895:Transposases / Q000378:metabolism
chemical_list: D019895:Transposases; C494471:sleeping beauty transposase, human