PDF(Pubmed)
Abstract：
Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of a subgroup of such leukemias with CpG Island Methylator Phenotype. These leukemias exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are defined by their shared epigenetic profile rather than common genetic lesions. Gene expression enrichment reveals similarity with early T-cell precursor acute lymphoblastic leukemia and a lymphoid progenitor cell of origin. In line with this, integration of differential DNA methylation and gene expression shows widespread silencing of myeloid transcription factors. Moreover, binding sites for hematopoietic transcription factors, including CEBPA, SPI1 and LEF1, are uniquely inaccessible in these leukemias. Hypermethylation also results in loss of CTCF binding, accompanied by changes in chromatin interactions involving key transcription factors. In conclusion, epigenetic dysregulation, and not genetic lesions, explains the mixed phenotype of this group of leukemias with ambiguous lineage. The data collected here constitute a useful and comprehensive epigenomic reference for subsequent studies of acute myeloid leukemias, T-cell acute lymphoblastic leukemias and mixed-phenotype leukemias.
摘要：
谱系模糊的白血病包括几个松散定义的实体，往往没有明确的机械基础。这里,我们广泛分析了CpG岛甲基化表型的此类白血病的一个亚组的表观基因组和转录组。这些白血病表现出相当的混合髓样/淋巴样表观遗传景观，然而异质性遗传改变，这表明它们是由它们共同的表观遗传特征而不是常见的遗传病变定义的。基因表达富集揭示了与早期T细胞前体急性淋巴细胞白血病和淋巴祖细胞起源的相似性。与此相符,差异DNA甲基化和基因表达的整合显示了髓样转录因子的广泛沉默。此外，造血转录因子的结合位点，包括CEBPA,SPI1和LEF1在这些白血病中是唯一无法进入的。超甲基化也导致CTCF结合的丧失，伴随着涉及关键转录因子的染色质相互作用的变化。总之,表观遗传失调，而不是遗传损伤，解释了该组具有模糊谱系的白血病的混合表型。这里收集的数据为后续急性髓系白血病的研究提供了有用且全面的表观基因组参考，T细胞急性淋巴细胞白血病和混合表型白血病。
