RUNX Proteins Desensitize Multiple Myeloma to Lenalidomide via Protecting IKZFs From Degradation

Leukemia. 2019 Aug;33(8):2006-2021. doi: 10.1038/s41375-019-0403-2. Epub 2019 Feb 13.

Abstract

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation, and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Core Binding Factor alpha Subunits / antagonists & inhibitors
  • Core Binding Factor alpha Subunits / chemistry
  • Core Binding Factor alpha Subunits / physiology*
  • Humans
  • Ikaros Transcription Factor / metabolism*
  • Lenalidomide / therapeutic use*
  • Multiple Myeloma / drug therapy*
  • Peptide Hydrolases / physiology

Substances

  • CRBN protein, human
  • Core Binding Factor alpha Subunits
  • IKZF1 protein, human
  • IKZF3 protein, human
  • Ikaros Transcription Factor
  • Peptide Hydrolases
  • Lenalidomide