Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia.

Autor: Adamo A; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Chin P; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Keane P; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Assi SA; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Potluri S; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Kellaway SG; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Coleman D; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Ames L; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Ptasinska A; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Delwel HR; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Cockerill PN; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK., Bonifer C; Institute of Cancer and Genomic Sciences, University of Birmingham, B152TT, Birmingham, UK. c.bonifer@bham.ac.uk.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Jan; Vol. 37 (1), pp. 102-112. Date of Electronic Publication: 2022 Nov 04.
DOI: 10.1038/s41375-022-01744-5
Abstrakt: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by mutations in genes encoding transcriptional and epigenetic regulators together with signaling genes. It is characterized by a disturbance of differentiation and abnormal proliferation of hematopoietic progenitors. We have previously shown that each AML subtype establishes its own core gene regulatory network (GRN), consisting of transcription factors binding to their target genes and imposing a specific gene expression pattern that is required for AML maintenance. In this study, we integrate gene expression, open chromatin and ChIP data with promoter-capture Hi-C data to define a refined core GRN common to all patients with CEBPA-double mutant (CEBPA N/C ) AML. These mutations disrupt the structure of a major regulator of myelopoiesis. We identify the binding sites of mutated C/EBPα proteins in primary cells, we show that C/EBPα, AP-1 factors and RUNX1 colocalize and are required for AML maintenance, and we employ single cell experiments to link important network nodes to the specific differentiation trajectory from leukemic stem to blast cells. Taken together, our study provides an important resource which predicts the specific therapeutic vulnerabilities of this AML subtype in human cells.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: