Plexiform neurofibroma genesis

Questions of Nf1 gene dose and hyperactive mast cells

Karl Staser, Feng Chun Yang, D. Clapp

Research output: Contribution to journalArticle

25 Citations (Scopus)

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

Fingerprint

Neurofibromatosis 1 Genes
Plexiform Neurofibroma
Mast Cells
Neurofibromatosis 1
Schwann Cells
Transplantation
Haploinsufficiency
Neurofibroma
Neoplasms
Mutation
Tumor Microenvironment
Gene Dosage
Tumor Suppressor Genes
Carcinogenesis
Bone Marrow
Alleles
Pharmacology
Inflammation

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

Plexiform neurofibroma genesis : Questions of Nf1 gene dose and hyperactive mast cells. / Staser, Karl; Yang, Feng Chun; Clapp, D.

In: Current Opinion in Hematology, Vol. 17, No. 4, 2010, p. 287-293.

Research output: Contribution to journalArticle

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