Infantile
myofibromatosis (IMF) is a benign
tumor form characterized by the development of nonmetastatic
tumors in skin, bone, muscle and sometimes viscera. Autosomal dominant forms of IMF are caused by mutations in the
PDGFRB gene, but a family carrying a L1519P mutation in the NOTCH3 gene has also recently been identified. In this report, we address the molecular consequences of the NOTCH3L1519P mutation and the relationship between the NOTCH and
PDGFRB signaling in IMF. The NOTCH3L1519P receptor generates enhanced downstream signaling in a
ligand-independent manner. Despite the enhanced signaling, the NOTCH3L1519P receptor is absent from the cell surface and instead accumulates in the endoplasmic reticulum. Furthermore, the localization of the NOTCH3L1519P receptor in the bipartite, heterodimeric state is altered, combined with avid secretion of the mutated extracellular domain from the cell.
Chloroquine treatment strongly reduces the amount of secreted NOTCH3L1519P extracellular domain and decreases signaling. Finally, NOTCH3L1519P upregulates
PDGFRB expression in fibroblasts, supporting a functional link between Notch and PDGF dysregulation in IMF. Collectively, our data define a NOTCH3-PDGFRB axis in IMF, where an IMF-mutated
NOTCH3 receptor elevates
PDGFRB expression. The functional characterization of a
ligand-independent gain-of-function NOTCH3 mutation is important for Notch
therapy considerations for IMF, including strategies aimed at altering lysosome function.