In-depth characterization of the microRNA transcriptome in a leukemia progression model.
MicroRNAs (miRNAs) have been shown to play important roles in physiological as well as multiple malignant processes, including acute myeloid leukemia (AML). In an effort to gain further insight into the role of miRNAs in AML, we have applied the Illumina massively parallel sequencing platform to carry out an in-depth analysis of the miRNA transcriptome in a murine leukemia progression model. This model simulates the stepwise conversion of a myeloid progenitor cell by an engineered overexpression of the nucleoporin 98 (NUP98)-homeobox HOXD13 fusion gene (ND13), to aggressive AML inducing cells upon transduction with the oncogenic collaborator Meis1. From this data set, we identified 307 miRNA/miRNA species in the ND13 cells and 306 miRNA/miRNA species in ND13+Meis1 cells, corresponding to 223 and 219 miRNA genes. Sequence counts varied between two and 136,558, indicating a remarkable expression range between the detected miRNA species. The large number of miRNAs expressed and the nature of differential expression suggest that leukemic progression as modeled here is dictated by the repertoire of shared, but differentially expressed miRNAs. Our finding of extensive sequence variations (isomiRs) for almost all miRNA and miRNA species adds additional complexity to the miRNA transcriptome. A stringent target prediction analysis coupled with in vitro target validation revealed the potential for miRNA-mediated release of oncogenes that facilitates leukemic progression from the preleukemic to leukemia inducing state. Finally, 55 novel miRNAs species were identified in our data set, adding further complexity to the emerging world of small RNAs.
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Florian
F
Kuchenbauer
Ryan D
RD
Morin
Bob
B
Argiropoulos
Oleh I
OI
Petriv
Malachi
M
Griffith
Michael
M
Heuser
Eric
E
Yung
Jessica
J
Piper
Allen
A
Delaney
Anna-Liisa
AL
Prabhu
Yongjun
Y
Zhao
Helen
H
McDonald
Thomas
T
Zeng
Martin
M
Hirst
Carl L
CL
Hansen
Marco A
MA
Marra
R Keith
RK
Humphries
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005818:Genetic Engineering; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; D014157:Transcription Factors; C093350:nuclear pore complex protein 98