INTRODUCTION AND OBJECTIVES: CRLF2 overexpression (CRLF2-over) 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-over in B-ALL patients. MATERIAL AND METHODS: We included 126 diagnostic B-ALL cases from TARGET cohort and characterised their molecular profile based on WGS and RNA-seq data. The Limma voom package was used for identifying the differentially expressed (DE) lincRNAs in CRLF2-overexpressing patients based on their adjusted p-value (p < 0.05). Potential functions of DE lincRNAs were determined by using the online databases RNA Encyclopedia of RNA Interactomes (ENCORI, http://starbase.sysu.edu.cn/) and RNA-Protein Interaction (RPISeq, http://pridb.gdcb.iastate.edu/RPISeq/). Association analyses were also conducted using Wilcoxon test and p-value<0.05 were considered significant. GRCh37 - hg19 was used as reference genome throughout the analyses. RESULTS AND CONCLUSION: The DE analysis of 6,200 lincRNAs identified 3 up- and 4 down-regulated lincRNAs in CRLF2-high compared to CRLF2-low patients. RPISeq prediction showed a high probability of interaction, up to 0.85, between up-regulated lncRNAs (MIR146A and RP11-1134I14.8) and CRLF2 protein sequence. Genome-wide mapping of B lymphocyte cell line - GM12878 - revealed that chromatin markers within +/−10 kb of MIR3142HG TSS region with enhancer characteristics. Additionally, we observed similar TFBS for TBP, BCL11A and FOXM1 in the promoter region of both MIR3142HG and CRLF2. These transcription factors (TFs) were previously reported as altered within CRLF2-associated sub-network displaying significant activity in CRLF2-high patients. These preliminary results are part of an ongoing investigation, therefore these initial findings suggest a potential mechanistic role for these DE lncRNAs. In conclusion, our data will expand the understanding of CRLF2 gene expression regulation.