HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia
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HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia. / 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.
in: J CLIN INVEST, Jahrgang 124, Nr. 3, 01.03.2014, S. 1158-67.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia
AU - Bartholdy, Boris
AU - Christopeit, Maximilian
AU - Will, Britta
AU - Mo, Yongkai
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
AU - Steidl, Ulrich
N1 - Keine Zugehörigkeit zum UKE laut WOS. Geteilte Erstautorenschaft geprüft. http://www.jci.org/articles/view/71264
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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.
AB - 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.
KW - Cell Differentiation
KW - DNA Methylation
KW - Epigenesis, Genetic
KW - Hematopoietic Stem Cells
KW - Humans
KW - Kaplan-Meier Estimate
KW - Leukemia, Myeloid, Acute
KW - Prognosis
KW - Proportional Hazards Models
KW - Transcriptome
U2 - 10.1172/JCI71264
DO - 10.1172/JCI71264
M3 - SCORING: Journal article
C2 - 24487588
VL - 124
SP - 1158
EP - 1167
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 3
ER -