MicroRNA expression in cytogenetically normal acute myeloid leukemia.

Abstract

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.

• Authors: Guido Marcucci, Michael D Radmacher, Kati Maharry, Krzysztof Mrózek, Amy S Ruppert, Peter Paschka, Tamara Vukosavljevic, Susan P Whitman, Claudia D Baldus, Christian Langer, Chang-Gong Liu, Andrew J Carroll, Bayard L Powell, Ramiro Garzon, Carlo M Croce, Jonathan E Kolitz, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
• Journal: The New England journal of medicine (N Engl J Med) Vol. 358 Issue 18 Pg. 1919-28 (May 01 2008) ISSN: 1533-4406 [Electronic] United States
• PMID: 18450603 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2008 Massachusetts Medical Society.

Chemical References

• DNA-Binding Proteins
• ERG protein, human
• Genetic Markers
• MicroRNAs
• NPM1 protein, human
• Nuclear Proteins
• RNA Probes
• RNA, Neoplasm
• Trans-Activators
• Transcriptional Regulator ERG
• Nucleophosmin
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Adult
• Analysis of Variance
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic (genetics)
• Genetic Markers
• Genetic Predisposition to Disease
• Humans
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (genetics, pathology)
• MicroRNAs (metabolism)
• Middle Aged
• Mutation
• Nuclear Proteins (genetics)
• Nucleophosmin
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Proportional Hazards Models
• RNA Probes
• RNA, Neoplasm (metabolism)
• Trans-Activators (genetics, metabolism)
• Transcriptional Regulator ERG
• fms-Like Tyrosine Kinase 3 (genetics)