Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Oncode Institute, Utrecht, the Netherlands.
Nat Commun. 2024 Jul 7;15(1):5693. doi: 10.1038/s41467-024-49811-y.
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.
具有模糊谱系的白血病包括几个定义不明确的实体，通常没有明确的机制基础。在这里，我们广泛地对具有 CpG 岛甲基化表型的此类白血病的一个亚组进行了表观基因组和转录组分析。这些白血病表现出相似的混合髓系/淋巴样表观遗传景观，但遗传改变却具有异质性，这表明它们是由共同的表观遗传特征定义的，而不是共同的遗传病变。基因表达富集分析显示与早期 T 细胞前体急性淋巴细胞白血病和淋巴祖细胞起源相似。与此一致的是，差异 DNA 甲基化和基因表达的整合显示广泛的髓系转录因子沉默。此外，在这些白血病中，造血转录因子（包括 CEBPA、SPI1 和 LEF1）的结合位点是无法接近的。高甲基化还导致 CTCF 结合的丧失，并伴有涉及关键转录因子的染色质相互作用的改变。总之，表观遗传失调而不是遗传病变解释了这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、T 细胞急性淋巴细胞白血病和混合表型白血病的研究提供了有用且全面的表观基因组参考。
