Rewiring of the Transcription Factor Network in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous cancer associated with different patterns of gene expression determined by the nature of their DNA mutations. These mutations mostly act to deregulate gene expression by various mechanisms at the level of the nucleus. By performing genome-wide e...

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Bibliographic Details
Published in:Cancer informatics 2019, Vol.18, p.1176935119859863-1176935119859863
Main Authors: Assi, Salam A, Bonifer, Constanze, Cockerill, Peter N
Format: Article
Language:English
Subjects:
Activator protein 1
Acute myeloid leukemia
Binding sites
Cancer
Chromatin
Cooperation
Deoxyribonuclease
Deoxyribonucleic acid
Deregulation
DNA
Epigenetics
Gene expression
Gene regulation
Genomes
Kinases
Leukemia
Mutation
Myeloid leukemia
Networks
Proteins
Regulatory sequences
Runx1 protein
Stem cells
Studies
Transcription factors
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Summary:Acute myeloid leukemia (AML) is a highly heterogeneous cancer associated with different patterns of gene expression determined by the nature of their DNA mutations. These mutations mostly act to deregulate gene expression by various mechanisms at the level of the nucleus. By performing genome-wide epigenetic profiling of cis-regulatory elements, we found that AML encompasses different mutation-specific subclasses associated with the rewiring of the gene regulatory networks that drive differentiation into different directions away from normal myeloid development. By integrating epigenetic profiles with gene expression and chromatin conformation data, we defined pathways within gene regulation networks that were differentially rewired within each mutation-specific subclass of AML. This analysis revealed 2 major classes of AML: one class defined by mutations in signaling molecules that activate AP-1 via the mitogen-activated protein (MAP) kinase pathway and a second class defined by mutations within genes encoding transcription factors such as RUNX1/CBFβ and C/EBPα. By identifying specific DNA motifs protected from DNase I digestion at cis-regulatory elements, we were able to infer candidate transcription factors bound to these motifs. These integrated analyses allowed the identification of AML subtype-specific core regulatory networks that are required for AML development and maintenance, which could now be targeted in personalized therapies.
ISSN:1176-9351
1176-9351
DOI:10.1177/1176935119859863