MicroRNA expression in cytogenetically normal acute myeloid leukemia.
BACKGROUND
A role of microRNAs in cancer has recently been recognized. However, little is known about the role of microRNAs in acute myeloid leukemia (AML).


METHODS
Using microRNA expression profiling, we studied samples of leukemia cells from adults under the age of 60 years who had cytogenetically normal AML and high-risk molecular features--that is, an internal tandem duplication in the fms-related tyrosine kinase 3 gene (FLT3-ITD), a wild-type nucleophosmin (NPM1), or both. A microRNA signature that was associated with event-free survival was derived from a training group of 64 patients and tested in a validation group of 55 patients. For the latter, a microRNA compound covariate predictor (called a microRNA summary value) was computed on the basis of weighted levels of the microRNAs forming the outcome signature.


RESULTS
Of 305 microRNA probes, 12 (including 5 representing microRNA-181 family members) were associated with event-free survival in the training group (P<0.005). In the validation group, the microRNA summary value was inversely associated with event-free survival (P=0.03). In multivariable analysis, the microRNA summary value remained associated with event-free survival (P=0.04) after adjustment for the allelic ratio of FLT3-ITD to wild-type FLT3 and for the white-cell count. Using results of gene-expression microarray analysis, we found that expression levels of the microRNA-181 family were inversely correlated with expression levels of predicted target genes encoding proteins involved in pathways of innate immunity mediated by toll-like receptors and interleukin-1beta.


CONCLUSIONS
A microRNA signature in molecularly defined, high-risk, cytogenetically normal AML is associated with the clinical outcome and with target genes encoding proteins involved in specific innate-immunity pathways.
Marcucci
Guido
G
Division of Hematology and Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. guido.marcucci@osumc.edu
Radmacher
Michael D
MD
Maharry
Kati
K
Mrózek
Krzysztof
K
Ruppert
Amy S
AS
Paschka
Peter
P
Vukosavljevic
Tamara
T
Whitman
Susan P
SP
Baldus
Claudia D
CD
Langer
Christian
C
Liu
Chang-Gong
CG
Carroll
Andrew J
AJ
Powell
Bayard L
BL
Garzon
Ramiro
R
Croce
Carlo M
CM
Kolitz
Jonathan E
JE
Caligiuri
Michael A
MA
Larson
Richard A
RA
Bloomfield
Clara D
CD
D000328:Adult; D000704:Analysis of Variance; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D015347:RNA Probes; D012334:RNA, Neoplasm / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D004268:DNA-Binding Proteins; C072312:ERG protein, human; D005819:Genetic Markers; D035683:MicroRNAs; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D015347:RNA Probes; D012334:RNA, Neoplasm; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3