Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells

• Published in: Leukemia Vol. 29; no. 6; pp. 1279 - 1289
• Main Authors: Spencer, D H, Young, M A, Lamprecht, T L, Helton, N M, Fulton, R, O'Laughlin, M, Fronick, C, Magrini, V, Demeter, R T, Miller, C A, Klco, J M, Wilson, R K, Ley, T J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2015
• Subjects: Abnormalities; Acute myelocytic leukemia; Acute myeloid leukemia; Biomarkers, Tumor - genetics; Case-Control Studies; CD34 antigen; Chromatin; Chromosome Aberrations; Cytogenetics; Development and progression; DNA Methylation; Epigenetics; Epigenomics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene loci; Gene sequencing; Genes; Genes, Homeobox - genetics; Genetic aspects; Health aspects; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; High-Throughput Nucleotide Sequencing; HOX gene; Humans; Identification and classification; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Methylation; Myeloid leukemia; Progenitor cells; Quantitative trait loci; Real-Time Polymerase Chain Reaction; Regulatory mechanisms (biology); Regulatory sequences; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA, Messenger - genetics; Stem cells; Survival Rate; Transcription; Transcription (Genetics)
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.6

HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.