Complete characterization of the microRNAome in a patient with acute myeloid leukemia.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and have been implicated in the pathogenesis of cancer. In this study, we applied next generation sequencing techniques to comprehensively assess miRNA expression, identify genetic variants of miRNA genes, and screen for alterations in miRNA binding sites in a patient with acute myeloid leukemia. RNA sequencing of leukemic myeloblasts or CD34(+) cells pooled from healthy donors showed that 472 miRNAs were expressed, including 7 novel miRNAs, some of which displayed differential expression. Sequencing of all known miRNA genes revealed several novel germline polymorphisms but no acquired mutations in the leukemia genome. Analysis of the sequence of the 3'-untranslated regions (UTRs) of all coding genes identified a single somatic mutation in the 3'-UTR of TNFAIP2, a known target of the PML-RARα oncogene. This mutation resulted in translational repression of a reporter gene in a Dicer-dependent fashion. This study represents the first complete characterization of the "miRNAome" in a primary human cancer and suggests that generation of miRNA binding sites in the UTR regions of genes is another potential mechanism by which somatic mutations can affect gene expression.
Ramsingh
Giridharan
G
Deparment of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Koboldt
Daniel C
DC
Trissal
Maria
M
Chiappinelli
Katherine B
KB
Wylie
Todd
T
Koul
Sunita
S
Chang
Li-Wei
LW
Nagarajan
Rakesh
R
Fehniger
Todd A
TA
Goodfellow
Paul
P
Magrini
Vincent
V
Wilson
Richard K
RK
Ding
Li
L
Ley
Timothy J
TJ
Mardis
Elaine R
ER
Link
Daniel C
DC
D020413:3' Untranslated Regions / Q000235:genetics; D001665:Binding Sites; D020869:Gene Expression Profiling / Q000379:methods* / Q000639:trends; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D035683:MicroRNAs / Q000032:analysis*; D009154:Mutation; D017423:Sequence Analysis, RNA
D020413:3' Untranslated Regions; D035683:MicroRNAs