Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia

Eva Diffner, Dominik Beck, Emma Gudgin, Julie A I Thoms, Kathy Knezevic, Clare Pridans, Sam Foster, Debbie Goode, Weng Khong Lim, Lies Boelen, Klaus H Metzeler, Gos Micklem, Stefan K Bohlander, Christian Buske, Alan Burnett, Katrin Ottersbach, George S Vassiliou, Jake Olivier, Jason W H Wong, Berthold GöttgensBrian J Huntly, John E Pimanda

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)2289-300
Number of pages12
JournalBlood
Volume121
Issue number12
DOIs
Publication statusPublished - 21 Mar 2013

Keywords

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cells, Cultured
  • Core Binding Factor Alpha 2 Subunit
  • Enhancer Elements, Genetic
  • GATA2 Transcription Factor
  • Gene Expression Regulation, Leukemic
  • Hematopoietic Stem Cells
  • Humans
  • K562 Cells
  • LIM Domain Proteins
  • Leukemia, Myeloid, Acute
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins
  • Neoplastic Stem Cells
  • Prognosis
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Activation

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