Tumor and Stem Cell Biology Perinatal or Adult Nf1 Inactivation Using Tamoxifen- Inducible PlpCre Each Cause Neurofibroma Formation

Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, whereas loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100bþmyelinating Schwann cells, and peripheral nerve p75þ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAPþ nonmyelinating Schwann cells. Extramedullary lymphohematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFPþ/Sca-1þ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibromainitiating cell populations. Cancer Res; 71(13); 4675–85. 2011 AACR.