Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow.
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.
Yang
Feng-Chun
FC
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Ingram
David A
DA
Chen
Shi
S
Zhu
Yuan
Y
Yuan
Jin
J
Li
Xiaohong
X
Yang
Xianlin
X
Knowles
Scott
S
Horn
Whitney
W
Li
Yan
Y
Zhang
Shaobo
S
Yang
Yanzhu
Y
Vakili
Saeed T
ST
Yu
Menggang
M
Burns
Dennis
D
Robertson
Kent
K
Hutchins
Gary
G
Parada
Luis F
LF
Clapp
D Wade
DW
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
D001549:Benzamides; D025542:Neurofibromin 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit