title: Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.
abstract: Aberrant transcriptional programs in combination with abnormal proliferative signaling drive leukemic transformation. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. Ets Related Gene (ERG) is a component of normal and leukemic stem cell signatures and high ERG expression is a risk factor for poor prognosis in acute myeloid leukemia (AML). However, mechanisms that underlie ERG expression in AML and how its expression relates to leukemic stemness are unknown. We report that ERG expression in AML is associated with activity of the ERG promoters and +85 stem cell enhancer and a heptad of transcription factors that combinatorially regulate genes in HSCs. Gene expression signatures derived from ERG promoter-stem cell enhancer and heptad activity are associated with clinical outcome when ERG expression alone fails. We also show that the heptad signature is associated with AMLs that lack somatic mutations in NPM1 and confers an adverse prognosis when associated with FLT3 mutations. Taken together, these results suggest that transcriptional regulators cooperate to establish or maintain primitive stem cell-like signatures in leukemic cells and that the underlying pattern of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome.
authors: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors: Eva
authors: E
authors: Diffner
authors: Dominik
authors: D
authors: Beck
authors: Emma
authors: E
authors: Gudgin
authors: Julie A I
authors: JA
authors: Thoms
authors: Kathy
authors: K
authors: Knezevic
authors: Clare
authors: C
authors: Pridans
authors: Sam
authors: S
authors: Foster
authors: Debbie
authors: D
authors: Goode
authors: Weng Khong
authors: WK
authors: Lim
authors: Lies
authors: L
authors: Boelen
authors: Klaus H
authors: KH
authors: Metzeler
authors: Gos
authors: G
authors: Micklem
authors: Stefan K
authors: SK
authors: Bohlander
authors: Christian
authors: C
authors: Buske
authors: Alan
authors: A
authors: Burnett
authors: Katrin
authors: K
authors: Ottersbach
authors: George S
authors: GS
authors: Vassiliou
authors: Jake
authors: J
authors: Olivier
authors: Jason W H
authors: JW
authors: Wong
authors: Berthold
authors: B
authors: Göttgens
authors: Brian J
authors: BJ
authors: Huntly
authors: John E
authors: JE
authors: Pimanda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000502:physiology; D000090243:Nucleophosmin; D011379:Prognosis; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050989:GATA2 Transcription Factor; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D000090243:Nucleophosmin; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C072312:ERG protein, human; C078433:FLI1 protein, human; C494711:GATA2 protein, human; C085117:LMO2 protein, human; C086541:LYL1 protein, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C493728:RUNX1 protein, human; C067143:TAL1 protein, human