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Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

Florian Grebien1,2, Masoud Vedadi3,4, Matthäus Getlik5

  • 1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.

Nature Chemical Biology
|July 14, 2015
PubMed

Insights

Mutations in the CEBPA gene are common in acute myeloid leukemia (AML). A specific C/EBPα isoform (p30) drives AML by interacting with Wdr5, offering a new therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Hematology

Background:

  • CCAAT-enhancer binding protein-α (C/EBPα) mutations, particularly the p30 isoform, are prevalent in acute myeloid leukemia (AML).
  • The precise mechanisms by which the p30 isoform drives leukemogenesis are not fully elucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms of p30-mediated transformation in AML.
  • To identify potential therapeutic targets for CEBPA-mutant AML.

Main Methods:

  • Investigated the interaction between C/EBPα p30 and Wdr5, a component of SET/MLL histone-methyltransferase complexes.
  • Analyzed MLL-dependent H3K4me3 marks in p30-bound genomic regions.
  • Assessed the role of Wdr5 in p30-driven proliferation and differentiation using gene downregulation.
  • Evaluated the efficacy of a novel Wdr5-MLL interaction antagonist (OICR-9429) in p30-expressing AML cells.

Main Results:

  • C/EBPα p30 preferentially interacts with Wdr5, unlike the normal p42 isoform.
  • p30-bound regions show enrichment of MLL-dependent H3K4me3 marks.
  • Wdr5 is essential for p30-induced increased self-renewal and inhibited myeloid differentiation.
  • OICR-9429 selectively inhibited proliferation and induced differentiation in p30-positive AML cells.

Conclusions:

  • The study elucidates the mechanism of p30-mediated transformation in AML, highlighting the critical role of Wdr5.
  • Wdr5 is identified as a key cofactor and a promising therapeutic target for CEBPA-mutant AML.

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