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Retroviral Insertional Mutagenesis Identifies Genes that Collaborate with NUP98-HOXD13 during Leukemic Transformation
- Source :
- Cancer Research. 67:5148-5155
- Publication Year :
- 2007
- Publisher :
- American Association for Cancer Research (AACR), 2007.
-
Abstract
- The t(2;11)(q31;p15) chromosomal translocation results in a fusion between the NUP98 and HOXD13 genes and has been observed in patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia. We previously showed that expression of the NUP98-HOXD13 (NHD13) fusion gene in transgenic mice results in an invariably fatal MDS; approximately one third of mice die due to complications of severe pancytopenia, and about two thirds progress to a fatal acute leukemia. In the present study, we used retroviral insertional mutagenesis to identify genes that might collaborate with NHD13 as the MDS transformed to an acute leukemia. Newborn NHD13 transgenic mice and littermate controls were infected with the MOL4070LTR retrovirus. The onset of leukemia was accelerated, suggesting a synergistic effect between the NHD13 transgene and the genes neighboring retroviral insertion events. We identified numerous common insertion sites located near protein-coding genes and confirmed dysregulation of a subset of these by expression analyses. Among these genes were Meis1, a known collaborator of HOX and NUP98-HOX fusion genes, and Mn1, a transcriptional coactivator involved in human leukemia through fusion with the TEL gene. Other putative collaborators included Gata2, Erg, and Epor. Of note, we identified a common insertion site that was >100 kb from the nearest coding gene, but within 20 kb of the miR29a/miR29b1 microRNA locus. Both of these miRNA were up-regulated, demonstrating that retroviral insertional mutagenesis can target miRNA loci as well as protein-coding loci. Our data provide new insights into NHD13-mediated leukemogenesis as well as retroviral insertional mutagenesis mechanisms. [Cancer Res 2007;67(11):5148–55]
- Subjects :
- ERG1 Potassium Channel
Cancer Research
Oncogene Proteins, Fusion
Mice, Transgenic
Article
Insertional mutagenesis
Fusion gene
Mice
Retrovirus
hemic and lymphatic diseases
medicine
Animals
Insertion
Cloning, Molecular
Myeloid Ecotropic Viral Integration Site 1 Protein
Hox gene
Gene
Homeodomain Proteins
Oncogene Proteins
Genetics
Acute leukemia
biology
Tumor Suppressor Proteins
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
biology.organism_classification
Ether-A-Go-Go Potassium Channels
Neoplasm Proteins
GATA2 Transcription Factor
Nuclear Pore Complex Proteins
MicroRNAs
Mutagenesis, Insertional
Leukemia
Cell Transformation, Neoplastic
Oncology
Leukemia, Myeloid
NIH 3T3 Cells
Trans-Activators
Cancer research
Moloney murine leukemia virus
Transcription Factors
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 67
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....c42d175d725721dec182b2530dd4c7c9