期刊
CURRENT OPINION IN HEMATOLOGY
卷 17, 期 4, 页码 287-293出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MOH.0b013e328339511b
关键词
c-kit; mast cells; neurofibroma; neurofibromatosis type 1; tumor microenvironment
类别
资金
- National Institutes of Health (NIH)-National Cancer Institute [RO1 CA074177-11A1/D, P50 NS052606-04, W81XWH-05-1-0161]
- National Institutes of Health [T32 CA111198]
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.
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