Long noncoding RNAs (lncRNAs) are defined as RNA transcripts that are larger than 200 nt but do not appear to have protein-coding potential. Cumulative evidence points towards an important role of lncRNAs in cancer initiation, development, and progression. In this study we sought to evaluate the lncRNA expression profile of patients with cytogenetically normal acute myeloid leukemia (CN-AML). RNA sequencing of forty CN-AML patients allowed us to identify more than 8000 previously-undescribed lncRNAs. Using unsupervised analysis we observed a specific lncRNA signature dependent on the mutational status of the nucleophosmin (NPM1) gene. Sparse partial least squares discriminant analysis allowed us to identify a minimal set of 19 lncRNAs capable of discriminating NPM1-mutated from NPM1-wild type patients. Among these, we found that expression of the XLOC_087120 lncRNA inversely correlates with its neighboring histone-coding genes. XLOC_087120 also interacts with SUZ12, a component of the Polycomb Repressive Complex 2, suggesting a role for this lncRNA in the epigenetic repression of histone genes and therefore a potential impact on chromatin remodeling. Indeed, its overexpression in cell lines leads to a downregulation of histone genes. Furthermore, we demonstrated that mutant NPM1 modulates the nuclear/cytoplasmic localization of XLOC_087120. Altogether, these data suggest that lncRNAs should be considered as key players in the pathogenesis of acute myeloid leukemias.
Citation Format: Etienne De Clara, Hanjing Ma, François Vergez, Cathy Quelen, Sébastien Dejean, Cécile Demur, Eric Delabesse, Christian Recher, Christian Touriol, Maria Paola Martelli, Brunangelo Falini, Pierre Brousset, Marina Bousquet. Long noncoding RNA expression in cytogenetically normal acute myeloid leukemia identifies a distinct signature associated with NPM1 mutations. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A27.