Lenalidomide-mediated enhanced translation of C/EBPa-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia.

Hickey CJ, Schwind S, Radomska HS, Dorrance AM, Santhanam R, Mishra A, Wu YZ, Alachkar H, Maharry K, Nicolet D, Mrózek K, Walker A, Eiring AM, Whitman SP, Becker H, Perrotti D, Wu LC, Zhao X, Fehniger TA, Vij R, Byrd JC, Blum W, Lee LJ, Caligiuri MA, Bloomfield CD, Garzon R, Marcucci G
Blood 121 159-69 01/03/2013

Abstract

Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPa transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPa-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPa-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPa-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.

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