ARID2 is a pomalidomide-dependent CRL4 CRBN substrate in multiple myeloma cells

Nat Chem Biol. 2020 Nov;16(11):1208-1217. doi: 10.1038/s41589-020-0645-3. Epub 2020 Sep 21.

Abstract

The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4CRBN. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Lenalidomide / pharmacology
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Mutation
  • Protein Binding
  • Proteolysis / drug effects
  • RNA, Messenger
  • RNA, Small Interfering
  • Thalidomide / analogs & derivatives*
  • Thalidomide / metabolism
  • Thalidomide / pharmacology
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • ARID2 protein, human
  • Antineoplastic Agents
  • BRD7 protein, human
  • Chromosomal Proteins, Non-Histone
  • RNA, Messenger
  • RNA, Small Interfering
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • Thalidomide
  • pomalidomide
  • Ubiquitin-Protein Ligases
  • CRL4 protein, human
  • Lenalidomide