title: Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Spencer
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Young
authors.affiliation: Department of Internal Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Lamprecht
authors.affiliation: Department of Internal Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Helton
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fulton
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fronick
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: V
authors.initials: V
authors.lastname: Magrini
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Demeter
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Klco
authors.affiliation: The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: 1] Department of Internal Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University School of Medicine, St Louis, MO, USA [2] The Genome Institute, Washington University, St Louis, MO, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D019175:DNA Methylation; D057890:Epigenomics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger