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

Boris A. 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 K. Verma, Ulrich G. Steidl

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1158-1167
Number of pages10
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014

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Acute Myeloid Leukemia
Epigenomics
Methylation
Myeloid Progenitor Cells
Megakaryocyte-Erythroid Progenitor Cells
Stem Cells
Mutation
Survival
Cytosine
DNA Methylation
Transcriptome
Ligation
Cell Differentiation
Genome
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia. / Bartholdy, Boris A.; 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 K.; Steidl, Ulrich G.

In: Journal of Clinical Investigation, Vol. 124, No. 3, 03.03.2014, p. 1158-1167.

Research output: Contribution to journalArticle

Bartholdy, BA, Christopeit, M, Will, B, Mo, Y, Barreyro, L, Yu, Y, Bhagat, TD, Okoye-Okafor, UC, Todorova, TI, Greally, JM, Levine, RL, Melnick, A, Verma, AK & Steidl, UG 2014, 'HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1158-1167. https://doi.org/10.1172/JCI71264
Bartholdy, Boris A. ; 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 K. ; Steidl, Ulrich G. / HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 3. pp. 1158-1167.
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AU - Christopeit, Maximilian

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AU - Barreyro, Laura

AU - Yu, Yiting

AU - Bhagat, Tushar D.

AU - Okoye-Okafor, Ujunwa C.

AU - Todorova, Tihomira I.

AU - Greally, John M.

AU - Levine, Ross L.

AU - Melnick, Ari

AU - Verma, Amit K.

AU - Steidl, Ulrich G.

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