Zhu Yuan Xiao, Braggio, Esteban, Shi Chang-Xin, Bruins Laura A, Schmidt Jessica E, Van Wier Scott, Chang Xiu-Bao, Bjorklund Chad C, Fonseca Rafael, Bergsagel P Leif, Orlowski Robert Z, Stewart A Keith "Blood 2011-Nov"
The exact molecular mechanism of motion and targets by means of which thalidomide and associated immunomodulatory medications (IMiDs) exert their antitumor results stays unclear.
We investigated the role of cereblon (CRBN), a primary teratogenic goal of thalidomide, within the antimyeloma activity of IMiDs. CRBN depletion is at first cytotoxic to human myeloma cells, but surviving cells with steady CRBN depletion turn into highly resistant to both lenalidomide and pomalidomide, although not for the unrelated medicines bortezomib, dexamethasone, and melphalan.
Acquired deletion of CRBN was discovered to become the primary genetic occasion differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were drastically suppressed within the presence of CRBN depletion, more demonstrating that CRBN is necessary for lenalidomide activity.
Downstream targets of CRBN contain interferon regulatory element 4 (IRF4) formerly reported to also be a target of lenalidomide. Individuals uncovered to, and putatively resistant to, lenalidomide had reduced CRBN ranges in paired samples before and after treatment.
In summary, CRBN is definitely an crucial requirement for IMiD exercise and a possible biomarker for your medical assessment of antimyeloma efficacy.
没有评论:
发表评论