HSC commitment associated epigenetic signature is prognostic in acute myeloid leukemia
HSC commitment associated epigenetic signature is prognostic in acute myeloid leukemia
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DOI：
10.1172/jci71264
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Steidl, Ulrich
中科院分区：
文献类型：
--
作者：
Bartholdy, Boris;Christopeit, Maximilian;Steidl, Ulrich
急性髓系白血病(AML)以HSC和祖细胞分化障碍为特征。通常，AML与编码表观遗传修饰因子的基因突变有关。我们假设，在健康的HSC承诺和分化过程中，对DNA甲基化模式变化的分析将产生表观遗传学特征，可用于识别AML分期特定的预后亚群。我们进行了纳米Hpall-tiny-fragment-enrichment-by-ligation-mediated-PCR(纳米HELP)分析，以比较高纯度的人类长期造血干细胞、短期造血干细胞、普通髓系祖细胞和巨核细胞-红系祖细胞的全基因组胞嘧啶甲基化情况。我们观察到，最显着的表观遗传学变化发生在短期HSC对普通髓系祖细胞的承诺期间，这些变化的主要特征是甲基化缺失。我们开发了一种与HSC承诺相关的甲基化模式的衡量标准，该模式被证明是3个独立的大型AML患者队列中总体生存的高度预后，而不考虑患者的治疗和表观遗传突变。应用表观遗传特征指标预测AML预后优于评估基于承诺的基因表达特征。总之，我们的数据定义了一个与干细胞承诺相关的甲基组，该甲基组独立地预示着AML较差的总体生存率。
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 Hpall-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 defme a stem cell commitment-associated methylome that is independently prognostic of poorer overall survival in AML.