Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia

Roger Mulet-Lazaro, Stanley Herk, Margit Nuetzel, Aniko Sijs-Szabo, Noelia Díaz, Katherine Kelly, Claudia Erpelinck-Verschueren, Lucia Schwarzfischer-Pfeilschifter, Hanna Stanewsky, Ute Ackermann, Dagmar Glatz, Johanna Raithel, Alexander Fischer, Sandra Pohl, Anita Rijneveld, Juan M. Vaquerizas, Christian Thiede, Christoph Plass, Bas J. Wouters (), Ruud Delwel (), Michael Rehli () and Claudia Gebhard ()
Additional contact information
Roger Mulet-Lazaro: Erasmus MC Cancer Institute
Stanley Herk: Erasmus MC Cancer Institute
Margit Nuetzel: University Hospital Regensburg
Aniko Sijs-Szabo: Erasmus MC Cancer Institute
Noelia Díaz: Max Planck Institute for Molecular Biomedicine
Katherine Kelly: German Cancer Research Center (DKFZ)
Claudia Erpelinck-Verschueren: Erasmus MC Cancer Institute
Lucia Schwarzfischer-Pfeilschifter: University Hospital Regensburg
Hanna Stanewsky: University Hospital Regensburg
Ute Ackermann: University Hospital Regensburg
Dagmar Glatz: University Hospital Regensburg
Johanna Raithel: University Hospital Regensburg
Alexander Fischer: University Hospital Regensburg
Sandra Pohl: University Hospital Regensburg
Anita Rijneveld: Erasmus MC Cancer Institute
Juan M. Vaquerizas: Max Planck Institute for Molecular Biomedicine
Christian Thiede: Universitätsklinikum Carl Gustav Carus
Christoph Plass: German Cancer Research Center (DKFZ)
Bas J. Wouters: Erasmus MC Cancer Institute
Ruud Delwel: Erasmus MC Cancer Institute
Michael Rehli: University Hospital Regensburg
Claudia Gebhard: University Hospital Regensburg

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49811-y

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