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

Assunta Adamo, Paulynn Chin, Peter Keane, Salam A. Assi, Sandeep Potluri, Sophie G. Kellaway, Daniel Coleman, Luke Ames, Anetta Ptasinska, H. Ruud Delwel, Peter N. Cockerill, Constanze Bonifer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 (CEBPAN/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.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalLeukemia
Volume37
Issue number1
DOIs
Publication statusPublished - 4 Nov 2022

Bibliographical note

Funding Information:
This work was funded by a studentship/development grant from Cancer Research UK, grants from the Medical Research Council (MR/S021469/1) and Blood Cancer UK (20006). We thank Genomics Birmingham for NGS sequencing and Mary Clarke for cell sorting.

Publisher Copyright:
© 2022, The Author(s).

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