HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia

• Published in: The Journal of clinical investigation Vol. 124; no. 3; pp. 1158 - 1167
• Main Authors: Bartholdy, Boris, Christopeit, Maximilian, Will, Britta, Mo, Yongkai, Barreyro, Laura, Yu, Yiting, Bhagat, Tushar D, Okoye-Okafor, Ujunwa C, Todorova, Tihomira I, Greally, John M, Levine, Ross L, Melnick, Ari, Verma, Amit, Steidl, Ulrich
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2014
• Subjects: Binding sites; Biomedical research; Cell Differentiation; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene expression; Genetic aspects; Genetic research; Genomes; Hematopoietic stem cells; Hematopoietic Stem Cells - physiology; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Medical research; MicroRNAs; Prognosis; Proportional Hazards Models; Software; Stem cells; Survival analysis; Transcriptome
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI71264

Acute myeloid leukemia (AML) is characterized by disruption of HSC and progenitor cell differentiation. Frequently, AML is associated with mutations in genes encoding epigenetic modifiers. We hypothesized that analysis of alterations in DNA methylation patterns during healthy HSC commitment and differentiation would yield epigenetic signatures that could be used to identify stage-specific prognostic subgroups of AML. We performed a nano HpaII-tiny-fragment-enrichment-by-ligation-mediated-PCR (nanoHELP) assay to compare genome-wide cytosine methylation profiles between highly purified human long-term HSC, short-term HSC, common myeloid progenitors, and megakaryocyte-erythrocyte progenitors. We observed that the most striking epigenetic changes occurred during the commitment of short-term HSC to common myeloid progenitors and these alterations were predominantly characterized by loss of methylation. We developed a metric of the HSC commitment–associated methylation pattern that proved to be highly prognostic of overall survival in 3 independent large AML patient cohorts, regardless of patient treatment and epigenetic mutations. Application of the epigenetic signature metric for AML prognosis was superior to evaluation of commitment-based gene expression signatures. Together, our data define a stem cell commitment–associated methylome that is independently prognostic of poorer overall survival in AML.