Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice

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 ET74A...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2019-04, Vol.9 (1), p.5488, Article 5488
Main Authors: Loeb, Keith R, Hughes, Bridget T, Fissel, Brian M, Osteen, Nyka J, Knoblaugh, Sue E, Grim, Jonathan E, Drury, Luke J, Sarver, Aaron, Dupuy, Adam J, Clurman, Bruce E
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
Animal models
Animals
Cancer
Cell culture
Cell Culture Techniques
Cell division
Cyclin E
Cyclin E - genetics
Disease Models, Animal
DNA Transposable Elements
E protein
Erythrocytes
Erythroleukemia
Erythropoiesis
Ets-1 protein
Genetic Predisposition to Disease
Hemopoiesis
Hyperactivity
Ikaros protein
Insertional mutagenesis
Leukemia
Leukemia, Erythroblastic, Acute - genetics
Leukemogenesis
Lymphocytes T
Lymphoma
Mice
Mutagenesis
Mutagenesis, Insertional
Myelodysplastic syndrome
Neoplasia
Notch1 protein
Oncogene Proteins - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Rodents
Therapeutic applications
Transcription factors
Transcriptional Regulator ERG - genetics
Transposase
Transposases - genetics
Transposons
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-41805-x