HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia
Boris Bartholdy, … , Amit Verma, Ulrich Steidl
Boris Bartholdy, … , Amit Verma, Ulrich Steidl
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(3):1158-1167. https://doi.org/10.1172/JCI71264.
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Research Article Oncology

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

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.

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

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Figure 2

Stem cell commitment–associated epigenetic signature is prognostic in AML.

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Stem cell commitment–associated epigenetic signature is prognostic in AM...
Application of the epigenetic signature to 3 independent published sets of patients with AML (4, 39–42). (A and B) Analysis of patients with AML who received standard chemotherapy. (C and D) Analysis of patients with AML who received chemotherapy with a higher dose of daunorubicin (DNR). (E) Analysis of the combined cohort of AML patients receiving standard or higher doses of daunorubicin (41). (G and H) Analysis of a third independent cohort of AML patients (39, 40). (A, C, and G) Heat maps of the respective patients (horizontal order) and the 561 loci (vertical order). Patients are ranked in descending order based on the signature score. Patients with high signature score are indicated by a green bar; patients with a low signature score by a black bar above the median-centered methylation heat map. (B, D, and E) Kaplan-Meier survival curves of OS of patients with AML are plotted. Green solid lines represent OS of patients with a high signature score; black solid lines represent OS of patients with a low signature score. (F) Overlay of survival curves from B and D. Black/red lines: patients with a low epigenetic stem cell commitment–associated signature score receiving standard or high dose daunorubicin treatment. Green/blue lines: patients with a high epigenetic stem cell commitment–associated signature score receiving standard or high dose daunorubicin treatment.