Plexiform neurofibroma genesis: Questions of Nf1 gene dose and hyperactive mast cells

Karl Staser, Feng Chun Yang, David W. Clapp

Research output: Contribution to journalReview article

26 Scopus citations

Abstract

Purpose of review: 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. Recent findings: 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. Summary: 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 haploinsufficient 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.

Original languageEnglish (US)
Pages (from-to)287-293
Number of pages7
JournalCurrent Opinion in Hematology
Volume17
Issue number4
DOIs
StatePublished - Jul 2010

Keywords

  • c-kit
  • mast cells
  • neurofibroma
  • neurofibromatosis type 1
  • tumor microenvironment

ASJC Scopus subject areas

  • Hematology

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