Effects of lenalidomide on CLL cells in vivo. Treatment with lenalidomide impacts PI3K, NFAT, and NFkB signaling, thereby inducing expression of CD154 that allows interaction of the CLL cells with T cells and activation of these T cells. At the same time, the chemoattractants CCL3 and CCL4 are deregulated on treatment with lenalidomide, with patients responding to therapy showing a down-regulation. Together with the observed induction of antibody production in CLL patients after therapy with lenalidomide, probably produced by nonmalignant B cells, these effects point toward re-establishment of a functional microenvironment by lenalidomide. The role of BCR signaling in this process is underlined by the fact that patients with unmutated IGHV genes and potentially active BCR signaling show a better response to lenalidomide treatment. However, patients with del(17p) had a poor outcome when treated with lenalidomide in the current study,1 suggesting that the major well-defined cause of treatment resistance in CLL (TP53 deletion/mutation) is not overcome.
