HSC Commitment-associated Epigenetic Signature is Prognostic in Acute Myeloid Leukemia

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2014 Feb 4

PMID 24487588

Citations 19

Authors

Boris Bartholdy

Maximilian Christopeit

Britta Will

Yongkai Mo

Laura Barreyro

Yiting Yu

Tushar D Bhagat

Ujunwa C Okoye-Okafor

Tihomira I Todorova

John M Greally

Ross L Levine

Ari Melnick

Amit Verma

Ulrich Steidl

Affiliations

Soon will be listed here.

Abstract

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.

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