Abstract
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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in western countries
We examined the regulatory potential of SNPs in linkage disequilibrium (LD) with rs2239630 using chromatin state modelling [36] in primary B-cells, showing lead SNPs reside in an active promoter
We examined whether 14q11.2 risk SNPs influence CCAT enhancerbinding protein epsilon (CEBPE) expression by performing expression quantitative trait loci analysis in ALL blast cells
Summary
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in western countries. Our understanding of ALL susceptibility has been transformed by genome-wide association studies (GWAS) [5,6,7,8]. GWAS have identified 11 loci associated with ALL, including the 14q11.2 risk locus, which has been replicated in multiple independent series [9, 10]. ALL risk loci often map in the vicinity of B-cell development genes, including IKZF1, GATA3, ARID5B and at 14q11.2 mapping to CCAT enhancerbinding protein epsilon (CEBPE) [6], suggesting a central role for dysregulated B-cell development in leukemogenesis. Crucial B-cell development transcription factors IKZF1, PAX5, and EBF1 are the targets of frequent somatic mutation [11, 12], highlighting that GWAS signals and somatic mutations may impact upon the same genes
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