title: Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow.
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.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.forename: Scott
authors.initials: S
authors.lastname: Knowles
authors.forename: Whitney
authors.initials: W
authors.lastname: Horn
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Shaobo
authors.initials: S
authors.lastname: Zhang
authors.forename: Yanzhu
authors.initials: Y
authors.lastname: Yang
authors.forename: Saeed T
authors.initials: ST
authors.lastname: Vakili
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Dennis
authors.initials: D
authors.lastname: Burns
authors.forename: Kent
authors.initials: K
authors.lastname: Robertson
authors.forename: Gary
authors.initials: G
authors.lastname: Hutchins
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000818:Animals; D001549:Benzamides; D001853:Bone Marrow / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009455:Neurofibroma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018318:Neurofibroma, Plexiform / Q000188:drug therapy / Q000378:metabolism; D025542:Neurofibromin 1 / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D012583:Schwann Cells / Q000378:metabolism
chemical_list: D001549:Benzamides; D025542:Neurofibromin 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit