title: Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia.
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/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-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/EBPα-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/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hickey
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Houda
authors.initials: H
authors.lastname: Alachkar
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Alison
authors.initials: A
authors.lastname: Walker
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D003561:Cytarabine / Q000494:pharmacology; D016368:Frameshift Mutation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D020014:K562 Cells; D000077269:Lenalidomide; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D007155:Immunologic Factors; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D003561:Cytarabine; D013792:Thalidomide; D000077269:Lenalidomide