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Previous Volume 358:1919-1928 May 1, 2008 Number 18 Next

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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-1β.

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.

Source Information

From the Comprehensive Cancer Center, Ohio State University, Columbus (G.M., M.D.R., K. Maharry, K. Mrózek, A.S.R., P.P., T.V., S.P.W., C.L., C.-G.L., R.G., C.M.C., M.A.C., C.D. Bloomfield); the Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, NC (M.D.R., K. Maharry, A.S.R.); Charité University Hospital, Berlin (C.D. Baldus); the University of Alabama at Birmingham, Birmingham (A.J.C.); the Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC (B.L.P.); the North Shore University Hospital, Manhasset, NY (J.E.K.); and the University of Chicago, Chicago (R.A.L.).

Drs. Marcucci and Radmacher contributed equally to this article.

Address reprint requests to Dr. Marcucci at the Division of Hematology and Oncology, Comprehensive Cancer Center, Ohio State University, Suite A434, Starling–Loving Hall, 320 W. 10th Ave., Columbus, OH 43210, or at guido.marcucci{at}osumc.edu.

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MicroRNA in Acute Myeloid Leukemia
Ritchie W. J., Flamant S., Rasko J. E.J., Marcucci G., Radmacher M. D., Bloomfield C. D.
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N Engl J Med 2008; 359:653-654, Aug 7, 2008. Correspondence

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