Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.

TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 and its regulatory partners (GATA3, RUNX1, and MYB) positively regulate each other and coordinately regulate the expression of their downstream target genes in T-ALL cells. However, long non-coding RNAs (lncRNAs) regulated by these factors are largely unknown. Here we established a bioinformatics pipeline and analyzed RNA-seq datasets with deep coverage to identify lncRNAs regulated by TAL1 in T-ALL cells. Our analysis predicted 57 putative lncRNAs that are activated by TAL1. Many of these transcripts were regulated by GATA3, RUNX1, and MYB in a coordinated manner. We identified two novel transcripts that were activated in multiple T-ALL cell samples but were downregulated in normal thymocytes. One transcript near the ARID5B gene locus was specifically expressed in TAL1-positive T-ALL cases. The other transcript located between the FAM49A and MYCN gene locus was also expressed in normal hematopoietic stem cells and T-cell progenitor cells. In addition, we identified a subset of lncRNAs that were negatively regulated by TAL1 and positively regulated by E-proteins in T-ALL cells. This included a known lncRNA (lnc-OAZ3-2:7) located near the RORC gene, which was expressed in normal thymocytes but repressed in TAL1-positive T-ALL cells.

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