Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells.
OBJECTIVE
Tumorigenic cells can co-opt normal functions of nonmalignant hematopoietic cells, promoting tumor progression. Recent mouse and human studies indicate that mast cells underpin inflammation in the plexiform neurofibroma microenvironment of neurofibromatosis type 1. In this model, Nf1 homozygous-deficient Schwann cells recruit hyperactive mast cells, promoting tumorigenesis. Here, we discuss the importance of Nf1 gene dosage, delineate hematopoietic contributions to the plexiform neurofibroma microenvironment, and highlight applications to human treatment.


RESULTS
Previous studies found that plexiform neurofibroma formation in a mouse model requires biallelic loss of Nf1 in Schwann cells and an Nf1 heterozygous cellular background. Now, transplantation and pharmacological experiments have indicated that tumor formation specifically requires Nf1 heterozygosity of c-kit-dependent bone marrow.


CONCLUSIONS
Neurofibromatosis type 1 results from autosomal dominant mutations of the NF1 tumor suppressor gene. Although unpredictable second-hit mutations in the remaining NF1 allele precede local manifestations such as tumor formation, human and mouse data indicate that NF1/Nf1 gene haploinsufficiency modulates cellular physiology and disease pathogeneses. In particular, Nf1 haplo insufficient mast cells demonstrate multiple gain-in-functions, and mast cells permeate neurofibroma tissue. Transplantation experiments have shown that these aberrant mast cells critically underpin the tumor microenvironment. Using these findings, clinicians have medically treated a patient with a debilitating plexiform neurofibroma.
Staser
Karl
K
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Yang
Feng-Chun
FC
Clapp
David W
DW
D000818:Animals; D020022:Genetic Predisposition to Disease; D006801:Humans; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008957:Models, Genetic; D018318:Neurofibroma, Plexiform / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology
D025542:Neurofibromin 1