Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemiawith MLL‑AF9 translocation

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLLAF9 translocation and identified potential new targets for the therapy of AML with MLLAF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLLAF9associated chromatin immunoprecipitation sequencing (ChIPSeq) data was analyzed and identified binding sites for MLLAF9 and wild type MLL (MLL WT). The ChIPSeq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLLAF9 leukemia cells and normal hematopoietic cells at MLLAF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLLAF9 direct target genes. Upon validation using RNASeq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLLAF9 were identified and further confirmed in MLLAF9 mouse model using reverse transcriptionquantitative polymerase chain reaction. These genes may have a critical role in AML with MLLAF9 translocation.