Figure 2.

Mechanism of action of lenalidomide in del(5q) MDS. (A) Lenalidomide directly inhibits Cdc25C, resulting in G2/M arrest and apoptosis in del(5q) cells. Lenalidomide also indirectly inhibits PP2A with consequent Cdc25C inactivation. (B) Reduced expression of RPS14 results in binding of free ribosomal proteins (RP) to MDM2, thereby triggering its auto-ubiquitination and p53 accumulation. Lenalidomide inhibition of the phosphatase PP2A results in hyperphosphorylation of MDM2 at Ser¹⁶⁶ and Ser¹⁸⁶ and stabilization of MDM2, with consequent p53 degradation and restored cell-cycle re-entry.