IMMUNOBIOLOGY

IMiDs immunomodulatory drugs, includ-ing lenalidomide and pomalidomide repre-sent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and pri-mary human monocytes, we report that pomalidomide rapidly and selectively ac-tivated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized mi-crotubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, poma-lidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalido-mide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the acti-vation of RhoA was essential for poma-lidomide-induced interleukin-2 expres-sion in T cells. These novel activities provide what we believe a critical mecha-nism by which IMiDs drugs function as therapeutic immunomodulatory agents. (Blood. 2009;114:338-345