Cell of origin strongly influences genetic selection in a mouse model of T-ALL

Katherine E. Berquam-Vrieze, Kishore Nannapaneni, Benjamin T. Brett, Linda Holmfeldt, Ma Jing, Oksana Zagorodna, Nancy A. Jenkins, Neal G. Copeland, David K. Meyerholz, C. Michael Knudson, Charles G. Mullighan, Todd E. Scheetz, Adam J. Dupuy

Research output: Contribution to journalArticle

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4646-4656
Number of pages11
JournalBlood
Volume118
Issue number17
DOIs
StatePublished - Oct 27 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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