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Nat Genet. 2019 Jan;51(1):151-162. doi: 10.1038/s41588-018-0270-1. Epub 2018 Nov 12.

Subtype-specific regulatory network rewiring in acute myeloid leukemia.

Author information

1
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
2
Northern Institute for Cancer Research, University of Newcastle, Newcastle, UK.
3
Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
4
West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
5
CMT Laboratory NHS Blood & Transplant, Edgbaston, Birmingham, UK.
6
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
7
Oncode Institute, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands.
8
Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds, UK.
9
Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK.
10
Princess Maxima Centrum for Pediatric Oncology, Utrecht, The Netherlands.
11
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. p.n.cockerill@bham.ac.uk.
12
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. c.bonifer@bham.ac.uk.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

PMID:
30420649
PMCID:
PMC6330064
[Available on 2019-05-12]
DOI:
10.1038/s41588-018-0270-1

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