Figure 1. Ptpn11E76K/+ mutation in Nestin+ MSPCs aberrantly activates neighbouring wild-type HSCs, inducing MPN in Ptpn11E76K/+Nestin-Cre+ mice.

According to the “2-hit” theory of Knudson, the first hit of the VHL syndrome is an inherited germline mutation of the VHL gene, whereas the development of HGB in VHL syndrome is caused by a second “hit” occurring in the tissue in which the tumor arises (15).

Loss of function of the VHL tumor suppressor gene is implicated in most cases of hemangioblastoma, both familial and sporadic.