Mutations of the Smad4 gene in acute myelogeneous leukemia and their functional implications in leukemogenesis

The Smad family proteins are critical components of the transforming growth factor (TGF)-β signaling pathway. TGF-β is a multipotent cytokine that elicits many biological functions. In particular, TGF-β exhibits effects on the cell cycle manifested by G1-phase arrest, differentiation, or apoptosis of several target cells, suggesting that disruption of TGF-β signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (Δ(483–552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The Δ(483–552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-β signaling. This is the first report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-β signaling pathway could lead to acute myelogeneous leukemia.