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Epigenetic landscape of mixed phenotype leukemias

Leukemias with ambiguous lineage comprise a number of loosely defined entities, often without a clear mechanistic basis. Here, we investigated a group of such leukemias with a CpG Island Methylator Phenotype (CIMP), previously identified as CEBPA-silenced AML. Transcriptomics and epigenomics analyses revealed a hybrid myeloid/lymphoid epigenetic landscape, whereas genetic alterations were heterogenous. This suggests that CIMP leukemias are defined by their shared epigenetic profile rather than a common genetic lesion. Gene expression enrichment showed strong similarity with ETP-ALL and an early lymphoid progenitor cell of origin. Accordingly, integration of differential methylation and expression revealed widespread silencing of myeloid transcription factors (TFs), among which CEBPA was key for differentiation arrest. Hypermethylation also resulted in loss of CTCF binding, accompanied by a few changes in chromatin interactions involving critical TFs like KLF4. In conclusion, epigenetic dysregulation, and not genetic lesions, explain the mixed phenotype of a group of CIMP leukemias resembling ETP-ALL.

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Dataset ID Description Technology Samples
EGAD00001011050 Illumina NovaSeq 6000 4
EGAD00001011051 Illumina NovaSeq 6000 3
EGAD00001011052 Illumina HiSeq 2500 36
EGAD00001011053 Illumina NovaSeq 6000 1
EGAD00001011054 Illumina NovaSeq 6000 81
EGAD00001011059 Illumina NovaSeq 6000 1
EGAD00001011060 Illumina HiSeq 2500 3