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Acute Leukemias

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.

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Acknowledgements

This work was supported by grants to DHS (CDP-1402, P50 CA171963-01 (D. Link, P.I.)), and TJL from the National Cancer Institute (P01CA101937 and R01CA162086). We thank the staff of The Genome Institute at Washington University for technical assistance. Technical assistance was also provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core, the High Speed Cell Sorting Core and the Molecular and Genomic Analysis Core at Washington University School of Medicine and Barnes-Jewish Hospital in St Louis, MO, which are all supported by the National Cancer Institute Cancer Center Support Grant P30CA91842. We also thank David Russler-Germain for critical reading of the manuscript.

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Spencer, D., Young, M., Lamprecht, T. et al. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells. Leukemia 29, 1279–1289 (2015). https://doi.org/10.1038/leu.2015.6

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