Oncotarget

Research Papers:

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

Marina Díaz-Beyá, Salut Brunet, Josep Nomdedéu, Marta Pratcorona, Anna Cordeiro, David Gallardo, Lourdes Escoda, Mar Tormo, Inmaculada Heras, Josep Maria Ribera, Rafael Duarte, María Paz Queipo de Llano, Joan Bargay, Antonia Sampol, Mertixell Nomdedeu, Ruth M. Risueño, Montserrat Hoyos, Jorge Sierra, Mariano Monzo, Alfons Navarro, Jordi Esteve _ and on behalf of the Cooperative AML group CETLAM

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Oncotarget. 2015; 6:31613-31627. https://doi.org/10.18632/oncotarget.5148

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Abstract

Marina Díaz-Beyá1,2, Salut Brunet2,3, Josep Nomdedéu2,4, Marta Pratcorona1,2, Anna Cordeiro5, David Gallardo6, Lourdes Escoda7, Mar Tormo8, Inmaculada Heras9, Josep Maria Ribera2,10, Rafael Duarte11, María Paz Queipo de Llano12, Joan Bargay13, Antonia Sampol14, Meritxell Nomdedeu1, Ruth M. Risueño2, Montserrat Hoyos3, Jorge Sierra2,3, Mariano Monzo5, Alfons Navarro5,*, Jordi Esteve1,2,15,*, on behalf of the Cooperative AML group CETLAM

1Hematology Department, Hospital Clinic, Institut d’Investigacions Bomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

2Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain

3Hematology 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

4Laboratory of Hematology Service, Institut d’Investigació Biomèdica Sant Pau. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

5Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain

6Hematology Department, Catalan Institute of Oncology (ICO), Girona, Spain

7Hematology Department, Hospital Joan XXIII, Tarragona, Spain

8Hematology Department, Hospital Clínico, Valencia, Spain

9University Hospital Morales Meseguer, Murcia, Spain

10Hematology Department, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Spain

11Department of Hematology, Catalan Institute of Oncology (ICO), Hospital Duran i Reynals, L’Hospitalet de Llobregat, Barcelona, Spain

12Hospital Virgen de la Victoria, Málaga, Spain

13Hospital de Son Llàtzer, Palma de Mallorca, Spain

14Hospital Son Espases, Palma de Mallorca, Spain

15University 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.


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