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Leukemia. 2019 Feb 13. doi: 10.1038/s41375-019-0403-2. [Epub ahead of print]

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation.

Author information

1
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Division of Hematology Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
The Stowers Institute for Medical Research, Kansas City, MO, USA.
4
Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA.
5
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
6
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. businol@upenn.edu.

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.

PMID:
30760870
DOI:
10.1038/s41375-019-0403-2

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