LncRNA Profiling Reveals That the Deregulation of H19, WT1-AS, TCL6, and LEF1-AS1 Is Associated with Higher-Risk Myelodysplastic Syndrome

SIMPLE SUMMARY: Although lncRNAs have been increasingly recognized as regulators of hematopoiesis, only several studies addressed their role in myelodysplastic syndrome (MDS). By genome-wide profiling, we identified lncRNAs deregulated in various groups of MDS patients. We computationally constructed lncRNA-protein coding gene networks to associate deregulated lncRNAs with cellular processes involved in MDS. We showed that expression of H19, WT1-AS, TCL6, and LEF1-AS1 lncRNAs associate with higher-risk MDS and proposed processes related with these transcripts. ABSTRACT: Background: myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder with an incompletely known pathogenesis. Long noncoding RNAs (lncRNAs) play multiple roles in hematopoiesis and represent a new class of biomarkers and therapeutic targets, but information on their roles in MDS is limited. Aims: here, we aimed to characterize lncRNAs deregulated in MDS that may function in disease pathogenesis. In particular, we focused on the identification of lncRNAs that could serve as novel potential biomarkers of adverse outcomes in MDS. Methods: we performed microarray expression profiling of lncRNAs and protein-coding genes (PCGs) in the CD34+ bone marrow cells of MDS patients. Expression profiles were analyzed in relation to different aspects of the disease (i.e., diagnosis, disease subtypes, cytogenetic and mutational aberrations, and risk of progression). LncRNA-PCG networks were constructed to link deregulated lncRNAs with regulatory mechanisms associated with MDS. Results: we found several lncRNAs strongly associated with disease pathogenesis (e.g., H19, WT1-AS, TCL6, LEF1-AS1, EPB41L4A-AS1, PVT1, GAS5, and ZFAS1). Of these, downregulation of LEF1-AS1 and TCL6 and upregulation of H19 and WT1-AS were associated with adverse outcomes in MDS patients. Multivariate analysis revealed that the predominant variables predictive of survival are blast count, H19 level, and TP53 mutation. Coexpression network data suggested that prognosis-related lncRNAs are predominantly related to cell adhesion and differentiation processes (H19 and WT1-AS) and mechanisms such as chromatin modification, cytokine response, and cell proliferation and death (LEF1-AS1 and TCL6). In addition, we observed that transcriptional regulation in the H19/IGF2 region is disrupted in higher-risk MDS, and discordant expression in this locus is associated with worse outcomes. Conclusions: we identified specific lncRNAs contributing to MDS pathogenesis and proposed cellular processes associated with these transcripts. Of the lncRNAs associated with patient prognosis, the level of H19 transcript might serve as a robust marker comparable to the clinical variables currently used for patient stratification.