The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs

Amit Mandoli, Abhishek A. Singh, Koen H.M. Prange, Esther Tijchon, Marjolein Oerlemans, Rene Dirks, Menno Ter Huurne, Albertus T.J. Wierenga, Eva M. Janssen-Megens, Kim Berentsen, Nilofar Sharifi, Bowon Kim, Filomena Matarese, Luan N. Nguyen, Nina C. Hubner, Nagesha A. Rao, Emile van den Akker, Lucia Altucci, Edo Vellenga, Hendrik G. Stunnenberg & 1 others Joost H.A. Martens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)

Abstract

The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.

Original languageEnglish
Pages (from-to)2087-2100
Number of pages14
JournalCell Reports
Volume17
Issue number8
DOIs
Publication statusPublished - 15 Nov 2016
Externally publishedYes

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Keywords

  • acute myeloid leukemia
  • AML1-ETO
  • apoptosis
  • epigenome
  • iPSC
  • RUNX1

Cite this

Mandoli, A., Singh, A. A., Prange, K. H. M., Tijchon, E., Oerlemans, M., Dirks, R., ... Martens, J. H. A. (2016). The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs. Cell Reports, 17(8), 2087-2100. https://doi.org/10.1016/j.celrep.2016.08.082