Data from Perinatal or Adult <i>Nf1</i> Inactivation Using Tamoxifen-Inducible <i>PlpCre</i> Each Cause Neurofibroma Formation

Abstract

<div>Abstract<p>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 <i>Nf1</i> loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of <i>Nf1</i> 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 <i>Nf1</i> loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ nonmyelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in <i>PlpCre;Nf1fl/fl</i> mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of <i>Nf1</i>-deleted microenvironment on lympho-hematopoietic proliferation <i>in vivo</i>. Together these findings define a tumor suppressor role for <i>Nf1</i> in the adult and narrow the range of potential neurofibroma-initiating cell populations. <i>Cancer Res; 71(13); 4675–85. ©2011 AACR</i>.</p></div>