title: Genome-wide analysis of transcriptional reprogramming in mouse models of acute myeloid leukaemia.
abstract: Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonadies
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Foster
authors.forename: Wai-In
authors.initials: WI
authors.lastname: Chan
authors.forename: Brynn T
authors.initials: BT
authors.lastname: Kvinlaug
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.forename: Elaine
authors.initials: E
authors.lastname: Spooncer
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bannister
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D050989:GATA2 Transcription Factor / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D006657:Histones; D014157:Transcription Factors