Yossi Cohen^1,, Odit Gutwein¹, Osnat Garach-Jehoshua², Adina Bar-Chaim³, Abraham Kornberg¹

Despite years of investigations, the mechanism of action of thalidomide and its derivatives is still unsolved. Recently we elaborated on the basis of the current literature data, including x-ray images of thalidomide victims, a hypothesis that premature differentiation of developing limb elements underlies the teratogenic effects of thalidomide and may also account for the antitumoral activity of the IMiDs. To examine the feasibility of this theory, we searched within gene expression profile datasets, which analyzed the changes induced by the IMiDs in myeloma cells, for supportive evidence. As expected, our analysis revealed a reproducible upregulation of a cluster of differentiating genes induced after either in-vivo or in-vitro treatment of the tumor-cells with thalidomide/ lenalidomide. This finding debates the long standing dogma that ascribed the teratogenic effect of thalidomide to apoptosis or toxic injury to limb bud mesenchyme/blood-vessels and places the IMiDs in line with differentiating teratogens like retinoids and related compounds.

Thalidomide, lenalidomide, dexamethasone, gene expression profile, PLSCR1, differentiation