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The lincRNA HOTAIRM1 , located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature

2015; Impact Journals LLC; Volume: 6; Issue: 31 Linguagem: Inglês

10.18632/oncotarget.5148

1949-2553

Marina Díaz‐Beyá, Salut Brunet, Josep Nomdedéu, Marta Pratcorona, Anna Cordeiro, David Gallardo, Lourdes Escoda, Mar Tormo, Inmaculada Heras, Josep‐María Ribera, Rafael F. Duarte, Maria Paz Queipo De Llano, Joan Bargay, Antònia Sampol, Meritxell Nomdedéu, Ruth M. Risueño, Montserrat Hoyos, Jorge Sierra, Mariano Monzó, Alfons Navarro, Jordi Esteve,

RNA Research and Splicing

// Marina Díaz-Beyá 1, 2 , Salut Brunet 2, 3 , Josep Nomdedéu 2, 4 , Marta Pratcorona 1, 2 , Anna Cordeiro 5 , David Gallardo 6 , Lourdes Escoda 7 , Mar Tormo 8 , Inmaculada Heras 9 , Josep Maria Ribera 2, 10 , Rafael Duarte 11 , María Paz Queipo de Llano 12 , Joan Bargay 13 , Antonia Sampol 14 , Meritxell Nomdedeu 1 , Ruth M. Risueño 2 , Montserrat Hoyos 3 , Jorge Sierra 2, 3 , Mariano Monzo 5 , Alfons Navarro 5, * , Jordi Esteve 1, 2, 15, * , on behalf of the Cooperative AML group CETLAM 1 Hematology Department, Hospital Clinic, Institut d’Investigacions Bomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 2 Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain 3 Hematology Service, Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Banc de Sang i Teixits de Catalunya, Spain 4 Laboratory of Hematology Service, Institut d’Investigació Biomèdica Sant Pau. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 5 Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain 6 Hematology Department, Catalan Institute of Oncology (ICO), Girona, Spain 7 Hematology Department, Hospital Joan XXIII, Tarragona, Spain 8 Hematology Department, Hospital Clínico, Valencia, Spain 9 University Hospital Morales Meseguer, Murcia, Spain 10 Hematology Department, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Spain 11 Department of Hematology, Catalan Institute of Oncology (ICO), Hospital Duran i Reynals, L’Hospitalet de Llobregat, Barcelona, Spain 12 Hospital Virgen de la Victoria, Málaga, Spain 13 Hospital de Son Llàtzer, Palma de Mallorca, Spain 14 Hospital Son Espases, Palma de Mallorca, Spain 15 University of Barcelona, Barcelona, Spain * These authors share the senior authorship Correspondence to: Jordi Esteve, e-mail: jesteve@clinic.ub.es Keywords: lincRNA, AML, HOTAIRM, HOX, lncRNA Received: July 20, 2015 Accepted: August 12, 2015 Published: September 11, 2015 ABSTRACT Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown. We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients. The lowest expression level was observed in acute promyelocytic leukemia ( P < 0.001) and the highest in t(6;9) AML ( P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04; P = 0.001), shorter leukemia-free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1 -mutated AML ( P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33-microRNA signature that included miR-196b ( P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR-196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004). Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature.