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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Zhou N,Gutierrez-Uzquiza A,Zheng XY,Chang R,Vogl DT,Garfall AL,Bernabei L,Saraf A,Florens L,Washburn MP,Illendula A,Bushweller JH,Busino Ldoi
10.1038/s41375-019-0403-2subject
Has Abstractpub_date
2019-08-01 00:00:00pages
2006-2021issue
8eissn
0887-6924issn
1476-5551pii
10.1038/s41375-019-0403-2journal_volume
33pub_type
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