Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation.
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.
Slape
Christopher
C
Genetics Branch, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20889-5105, USA.
Hartung
Helge
H
Lin
Ying-Wei
YW
Bies
Juraj
J
Wolff
Linda
L
Aplan
Peter D
PD
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003001:Cloning, Molecular; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D008979:Moloney murine leukemia virus / Q000235:genetics; D016254:Mutagenesis, Insertional; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; C000606915:Kcnh2 protein, mouse; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; C501081:Mn1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093350:nuclear pore complex protein 98