Journal article
Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice
Scientific reports, Vol.9(1), pp.5488-5488
04/02/2019
DOI: 10.1038/s41598-019-41805-x
PMCID: PMC6445099
PMID: 30940846
Abstract
Insertional mutagenesis is a powerful means of identifying cancer drivers in animal models. We used the Sleeping Beauty (SB) transposon/transposase system to identify activated oncogenes in hematologic cancers in wild-type mice and mice that express a stabilized cyclin E protein (termed cyclin ET74AT393A). Cyclin E governs cell division and is misregulated in human cancers. Cyclin ET74AT393A mice develop ineffective erythropoiesis that resembles early-stage human myelodysplastic syndrome, and we sought to identify oncogenes that might cooperate with cyclin E hyperactivity in leukemogenesis. SB activation in hematopoietic precursors caused T-cell leukemia/lymphomas (T-ALL) and pure red blood cell erythroleukemias (EL). Analysis of >12,000 SB integration sites revealed markedly different oncogene activations in EL and T-ALL: Notch1 and Ikaros were most common in T-ALL, whereas ETS transcription factors (Erg and Ets1) were targeted in most ELs. Cyclin E status did not impact leukemogenesis or oncogene activations. Whereas most SB insertions were lost during culture of EL cell lines, Erg insertions were retained, indicating Erg's key role in these neoplasms. Surprisingly, cyclin ET74AT393A conferred growth factor independence and altered Erg-dependent differentiation in EL cell lines. These studies provide new molecular insights into erythroid leukemia and suggest potential therapeutic targets for human leukemia.
Details
- Title: Subtitle
- Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice
- Creators
- Keith R Loeb - Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USABridget T Hughes - University of Utah, Salt Lake City, UT, USABrian M Fissel - Boston University School of Medicine, Boston, MA, USANyka J Osteen - Divisions of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USASue E Knoblaugh - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, 43210, USAJonathan E Grim - VA Puget Sound Health Care System, Seattle, WA, 98108, USALuke J Drury - Department of Anatomy & Cell Biology, University of Iowa, Iowa City, IA, 52242, USAAaron Sarver - Institute for Health Informatics, University of Minnesota, Minneapolis, MN, 55455, USAAdam J Dupuy - Department of Anatomy & Cell Biology, University of Iowa, Iowa City, IA, 52242, USABruce E Clurman - Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. bclurman@fredhutch.org
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.9(1), pp.5488-5488
- DOI
- 10.1038/s41598-019-41805-x
- PMID
- 30940846
- PMCID
- PMC6445099
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- England
- Grant note
- R50 CA211249 / NCI NIH HHS P30 CA015704 / NCI NIH HHS 1R21CA229922 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30 DK 56465 / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) P30 CA086862 / NCI NIH HHS R01 CA193808 / NCI NIH HHS R01 CA084069 / NCI NIH HHS
- Language
- English
- Date published
- 04/02/2019
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025410402771
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