title: Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature.
abstract: Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cauchy
authors.affiliation: Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Sally R
authors.initials: SR
authors.lastname: James
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Zacarias-Cabeza
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Anetta
authors.initials: A
authors.lastname: Ptasinska
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Imperato
authors.affiliation: Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Salam A
authors.initials: SA
authors.lastname: Assi
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Piper
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Canestraro
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hoogenkamp
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.
authors.forename: Manoj
authors.initials: M
authors.lastname: Raghavan
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Loke
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Akiki
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Clokie
authors.affiliation: Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Richards
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Westhead
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Griffiths
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ott
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.bonifer@bham.ac.uk.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: School of Immunity and Infection, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: p.n.cockerill@bham.ac.uk.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Cockerill
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; D018808:Transcription Factor AP-1; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases