TitleHSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsBartholdy, 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, and Steidl Ulrich
JournalJ Clin Invest
Volume124
Issue3
Pagination1158-67
Date Published2014 Mar
ISSN1558-8238
KeywordsCell Differentiation, DNA Methylation, Epigenesis, Genetic, Hematopoietic Stem Cells, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute, Prognosis, Proportional Hazards Models, Transcriptome
Abstract

<p>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.</p>

DOI10.1172/JCI71264
Alternate JournalJ Clin Invest
PubMed ID24487588
PubMed Central IDPMC3934187
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R00 CA131503 / CA / NCI NIH HHS / United States
R01 CA166429 / CA / NCI NIH HHS / United States
R00CA131503 / CA / NCI NIH HHS / United States