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

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.

A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells

“…Interestingly, NEAT1_2 expression tended to increase with advancing age (Figure S4). We therefore compared NEAT1 expression in CD34 + HSPCs from healthy people and patients with ASXL1-mutated myeloid neoplasms at ages 50-70 (Szikszai et al, 2020). Consistent with the mouse data, expression of NEAT1_2, but not total Neat1, was downregulated in human HSPCs with ASXL1 mutations (Figure 4D).…”

A novel ferroptosis-related lncRNA signature for prognosis prediction in gastric cancer

“…Interestingly, Wang, S et al built a novel prognostic nomogram based on five lnc-RNAs in clear cell renal cell carcinoma, comprising AC026992.2, AC245041.2, LINC00524, LINC01956, and LINC02080 [ 46 ]. Previous work on lncRNA profiling also revealed that BOLA3-AS1 was associated with higher-risk myelodysplastic syndrome, which played an important role in the development of blood lineages such as platelets, erythrocytes, and myeloid cells [ 47 ]. However, the roles of AP003392.1 and AP001271.1 are yet unknown.…”

Emodin inhibits the progression of acute pancreatitis via regulation of lncRNA TUG1 and exosomal lncRNA TUG1

“…Long non-coding RNAs (lncRNAs) can play important roles in the development of multiple diseases (11,12). Moreover, lncRNAs participate in the prevention of AP.…”