Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/-- and c-kit-Dependent Bone Marrow

Feng Chun Yang, David A. Ingram, Shi Chen, Yuan Zhu, Jin Yuan, Xiaohong Li, Xianlin Yang, Scott Knowles, Whitney Horn, Yan Li, Shaobo Zhang, Yanzhu Yang, Saeed T. Vakili, Menggang Yu, Dennis Burns, Kent Robertson, Gary Hutchins, Luis F. Parada, D. Wade Clapp

Research output: Contribution to journalArticlepeer-review

245 Scopus citations

Abstract

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalCell
Volume135
Issue number3
DOIs
StatePublished - Oct 31 2008
Externally publishedYes

Keywords

  • CELLCYCLE
  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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