Whole-body sleeping beauty mutagenesis can cause penetrant leukemia/lymphoma and rare high-grade glioma without associated embryonic lethality

Lara S. Collier, David J. Adams, Christopher S. Hackett, Laura E. Bendzick, Keiko Akagi, Michael N. Davies, Miechaleen D. Diers, Fausto J. Rodriguez, Aaron M. Bender, Christina Tieu, Ilze Matise, Adam J. Dupuy, Neal G. Copeland, Nancy A. Jenkins, J. Graeme Hodgson, William A. Weiss, Robert B. Jenkins, David A. Largaespada

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The Sleeping Beauty (SB) transposon system has been used as a somatic mutagen to identify candidate cancer genes. In previous studies, efficient leukemia/lymphoma formation on an otherwise wild-type genetic background occurred in mice undergoing whole-body mobilization of transposons, but was accompanied by high levels of embryonic lethality. To explore the utility of SB for large-scale cancer gene discovery projects, we have generated mice that carry combinations of different transposon and transposase transgenes. We have identified a transposon/transposase combination that promotes highly penetrant leukemia/lymphoma formation on an otherwise wild-type genetic background, yet does not cause embryonic lethality. Infiltrating gliomas also occurred at lower penetrance in these mice. SB-induced or accelerated tumors do not harbor large numbers of chromosomal amplifications or deletions, indicating that transposon mobilization likely promotes tumor formation by insertional mutagenesis of cancer genes, and not by promoting wide-scale genomic instability. Cloning of transposon insertions from lymphomas/ leukemias identified common insertion sites at known and candidate novel cancer genes. These data indicate that a high mutagenesis rate can be achieved using SB without high levels of embryonic lethality or genomic instability. Furthermore, the SB system could be used to identify new genes involved in lymphomagenesis/leukemogenesis.

Original languageEnglish (US)
Pages (from-to)8429-8437
Number of pages9
JournalCancer research
Volume69
Issue number21
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Whole-body sleeping beauty mutagenesis can cause penetrant leukemia/lymphoma and rare high-grade glioma without associated embryonic lethality'. Together they form a unique fingerprint.

  • Cite this

    Collier, L. S., Adams, D. J., Hackett, C. S., Bendzick, L. E., Akagi, K., Davies, M. N., Diers, M. D., Rodriguez, F. J., Bender, A. M., Tieu, C., Matise, I., Dupuy, A. J., Copeland, N. G., Jenkins, N. A., Hodgson, J. G., Weiss, W. A., Jenkins, R. B., & Largaespada, D. A. (2009). Whole-body sleeping beauty mutagenesis can cause penetrant leukemia/lymphoma and rare high-grade glioma without associated embryonic lethality. Cancer research, 69(21), 8429-8437. https://doi.org/10.1158/0008-5472.CAN-09-1760