TAF1 Plays a Critical Role in AML1-ETO Driven Leukemogenesis

Nat Commun. 2019 Oct 29;10(1):4925. doi: 10.1038/s41467-019-12735-z.

Abstract

AML1-ETO (AE) is a fusion transcription factor, generated by the t(8;21) translocation, that functions as a leukemia promoting oncogene. Here, we demonstrate that TATA-Box Binding Protein Associated Factor 1 (TAF1) associates with K43 acetylated AE and this association plays a pivotal role in the proliferation of AE-expressing acute myeloid leukemia (AML) cells. ChIP-sequencing indicates significant overlap of the TAF1 and AE binding sites. Knockdown of TAF1 alters the association of AE with chromatin, affecting of the expression of genes that are activated or repressed by AE. Furthermore, TAF1 is required for leukemic cell self-renewal and its reduction promotes the differentiation and apoptosis of AE+ AML cells, thereby impairing AE driven leukemogenesis. Together, our findings reveal a role of TAF1 in leukemogenesis and identify TAF1 as a potential therapeutic target for AE-expressing leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Carcinogenesis / pathology*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Self Renewal
  • Chromatin / metabolism
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Gene Expression Regulation, Leukemic
  • Histone Acetyltransferases / chemistry
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology*
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Myeloid Cells / pathology
  • Oncogene Proteins, Fusion / metabolism*
  • Protein Binding
  • Protein Domains
  • RUNX1 Translocation Partner 1 Protein / metabolism*
  • TATA-Binding Protein Associated Factors / chemistry
  • TATA-Binding Protein Associated Factors / metabolism*
  • Transcription Factor TFIID / chemistry
  • Transcription Factor TFIID / metabolism*

Substances

  • AML1-ETO fusion protein, human
  • Chromatin
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • Histone Acetyltransferases
  • TATA-binding protein associated factor 250 kDa
  • Lysine