Subtype-specific regulatory network rewiring in acute myeloid leukemia

• Published in: Nature genetics Vol. 51; no. 1; pp. 151 - 162
• Main Authors: Assi, Salam A., Imperato, Maria Rosaria, Coleman, Daniel J. L., Pickin, Anna, Potluri, Sandeep, Ptasinska, Anetta, Chin, Paulynn Suyin, Blair, Helen, Cauchy, Pierre, James, Sally R., Zacarias-Cabeza, Joaquin, Gilding, L. Niall, Beggs, Andrew, Clokie, Sam, Loke, Justin C., Jenkin, Phil, Uddin, Ash, Delwel, Ruud, Richards, Stephen J., Raghavan, Manoj, Griffiths, Michael J., Heidenreich, Olaf, Cockerill, Peter N., Bonifer, Constanze
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2019; Nature Publishing Group
• Subjects: 13/106; 38/23; 38/39; 38/47; 38/89; 38/90; 38/91; 631/337/176; 64; 64/60; 692/699/67/1990/283/1897; Acute myelocytic leukemia; Acute myeloid leukemia; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blast cells; Cancer Research; Cell cycle; Cellular signal transduction; Chromatin; Data processing; Deoxyribonucleic acid; DNA; DNA binding proteins; DNA methylation; Epigenetic inheritance; Epigenetics; Explosions; Female; Gene expression; Gene Expression Regulation, Leukemic - genetics; Gene Function; Gene Regulatory Networks - genetics; Genes; Genetic aspects; Genetic engineering; Genomes; Human Genetics; Humans; Information management; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Lymphoma; Male; Middle Aged; Mutation; Myeloid leukemia; Nucleophosmin; Occupancy; Proteins; Regulators; Rewiring; Runx1 protein; Signal Transduction - genetics; Signaling; Stem cells; Subgroups; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Young Adult
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0270-1

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. Integrated analysis of transcriptome, open chromatin region and chromatin conformation capture data from subjects with acute myeloid leukemia (AML) harboring defined transcription factor and signaling molecule alterations provide insights into the subtype-specific regulatory network in AML.