NF1-DEFICIENT MOUSE SCHWANN-CELLS ARE ANGIOGENIC AND INVASIVE AND CANBE INDUCED TO HYPERPROLIFERATE - REVERSION OF SOME PHENOTYPES BY AN INHIBITOR OF FARNESYL-PROTEIN TRANSFERASE

We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells hete rozygous or null at Nf1 display angiogenic and invasive properties, mi micking the behavior of Schwann cells from human neurofibromas. Mutati ons at Nf1 are insufficient to promote Schwann cell hyperplasia, Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture mediu m also stimulates hyperplasia, but only in some mutant cells. After se rum removal, clones of hyperproliferating Schwann cells lose contact w ith axons in vitro, develop growth factor-independent proliferation, a nd exhibit decreased expression of the cell differentiation marker PO protein; hyperproliferating cells develop after a 1-week lag in Schwan n cells heterozygous at Nf1. The experiments suggest that events Subse quent to Nf1 mutations are required for development of Schwann cell hy perplasia, Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of nul l mutant cells, but not invasion; farnesyl transferase inhibitors coul d be useful in treating benign manifestations of NF1.