title: Biological activity of lenalidomide in myelodysplastic syndromes with del5q: results of gene expression profiling from a multicenter phase II study.
abstract: In vitro studies suggest that haploinsufficiency is involved in the pathogenesis of myelodysplastic syndromes (MDS). In patients with del5q cytogenetic abnormality, RPS-14 and microRNAs (miRNAs) play a major role. In a multicenter phase II single-arm trial with lenalidomide in anemic primary del5q MDS patients with low- or int-1 risk IPSS, biological changes from baseline were investigated. Gene expression profiling of selected genes was performed (TaqMan® Low Density Array Fluidic card, Applied Biosystems PRISM® 7900HT) and normalized against the expression of the 18S housekeeping gene from a pool of healthy subjects. Thirty-two patients were evaluated at baseline and after 3 and 6 months of treatment. RPS-14, miR-145, and miR-146 were downregulated at baseline and significantly increased during treatment. Nuclear factor kappa B, IL-6, interferon regulatory factor-1, IFNγ-R2, IL-2, and many genes in the apoptotic pathways (TNF, IL-1B, and IL-10) were upregulated at baseline and significantly downregulated during lenalidomide treatment, while forkhead box P3, FAS, IFNγ, IL-12A, and IL-12B were downregulated at baseline and progressively upregulated during treatment. The crucial role of aberrant immunological pathways and haploinsufficiency in the pathogenesis of del5q MDS is confirmed in the present patient setting. Our results indicate that lenalidomide may act through defined immunological pathways in this condition.
authors.affiliation: Haematology Unit, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Via Melacrino, 89100, Reggio, Calabria, Italy. enoliva@gmail.com
authors.forename: Esther Natalie
authors.initials: EN
authors.lastname: Oliva
authors.forename: Maria
authors.initials: M
authors.lastname: Cuzzola
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Aloe Spiriti
authors.forename: Antonella
authors.initials: A
authors.lastname: Poloni
authors.forename: Carmelo
authors.initials: C
authors.lastname: Laganà
authors.forename: Carmela
authors.initials: C
authors.lastname: Rigolino
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.forename: Sara
authors.initials: S
authors.lastname: Galimberti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ghio
authors.forename: Agostino
authors.initials: A
authors.lastname: Cortelezzi
authors.forename: Giuseppe Alberto
authors.initials: GA
authors.lastname: Palumbo
authors.forename: Grazia
authors.initials: G
authors.lastname: Sanpaolo
authors.forename: Carlo
authors.initials: C
authors.lastname: Finelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ricco
authors.forename: Antonio
authors.initials: A
authors.lastname: Volpe
authors.forename: Filippo
authors.initials: F
authors.lastname: Rodà
authors.forename: Massimo
authors.initials: M
authors.lastname: Breccia
authors.forename: Giuliana
authors.initials: G
authors.lastname: Alimena
authors.forename: Francesco
authors.initials: F
authors.lastname: Nobile
authors.forename: Roberto
authors.initials: R
authors.lastname: Latagliata
mesh_terms: D000368:Aged; D000748:Anemia, Macrocytic / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D056726:Genetic Association Studies; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D000077269:Lenalidomide; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D008957:Models, Genetic; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; C526722:RPS14 protein, human; D012269:Ribosomal Proteins; D013792:Thalidomide; D000077269:Lenalidomide