Proceedings of Oncobiology Symposiums
Proceedings of the XV Oncobiology Symposium

INTRODUCTION AND OBJECTIVES: CRLF2 overexpression (CRLF2-high) has been associated with unfavourable prognosis in acute lymphoblastic leukaemia (ALL) cases. In B-cell precursor ALL (B-ALL), the presence of CRLF2 rearrangements (CRLF2-r) and CRLF2 F232C mutations can explain half of the cases with this gene overexpression. Nonetheless, the mechanism accounting for the other 50% of cases lacking CRLF2 abnormalities is still unknown. Recent studies have suggested that long non-coding RNAs (lncRNAs), including intergenic lncRNAs (lincRNAs), play a role in the development and progression of leukaemia and can interfere in the transcriptional regulation of protein-coding genes. In this scenario, we hypothesise that the dysregulation of lncRNAs might be a potential mechanism behind CRLF2-high in B-ALL patients. MATERIAL AND METHODS: We included 126 diagnostic B-ALL cases from the TARGET cohort and characterised their molecular profile based on WGS and RNA-seq data. The DESeq2 v.1.28.1 package was used for identifying the differentially expressed (DE) lincRNAs in CRLF2-high patients based on their adjusted p-value (p < 0.05). Lncpath package was used to obtain functional pathways influenced by the combinatory effect of DE lincRNAs with an FDR < 0.05. The DE lncRNA mRNA pairs experimentally validated were obtained from the LncRNA2Target v3.0 database. The interactions identified were tested in the TARGET data using correlation analysis. In addition, potential miRNAs targets were predicted by the multimiR package. All analyses were conducted based on the GRCh37-hg19 genome. RESULTS AND CONCLUSION: The DE analysis of 6,200 lincRNAs identified 293 up- and 70 down-regulated lincRNAs in CRLF2-high compared to CRLF2-low patients. These DE lincRNAs are mainly involved in pathways of processing of genetic information as well as pathways involved in different types of cancer, including acute and chronic myeloid leukemia. The expression patterns of 5 out of 11 potential DE lncRNA-target relationships identified were positively correlated among them in TARGET B-ALL cohort (R > 0.10 and p < 0.05), including RPL34-AS1-MIR3663, LINC00161-MIR21, LINC00161-MIR590, PWRN1-MIR21 and PART1-MIR149. These lincRNAs were previously reported as competing endogenous RNA (ceRNA) via sponging these target miRNAs pointed in other type cancer cells, impacting in cell proliferation, invasion, migration and apoptosis. The prediction of candidate target miRNAs revealed more than 11,000 miRNA-mRNA interactions that are under investigation. Based on this initial data, we will validate the significant correlations observed in the preliminary analyses in a series of Brazilian B-ALL cases. Our initial findings suggest a potential mechanistic role for these lincRNAs interactions on leukemogenesis which could unravel potential biomarkers. In conclusion, our data will expand the understanding of CRLF2 gene expression regulation.