PT  - JOURNAL ARTICLE
AU  - Akira Inoue
AU  - Laura J. Janke
AU  - Brian L. Gudenas
AU  - Hongjian Jin
AU  - Yiping Fan
AU  - Joshua Paré
AU  - Michael R. Clay
AU  - Paul A. Northcott
AU  - Angela C. Hirbe
AU  - Xinwei Cao
TI  - A genetic mouse model with postnatal <em>Nf1</em> and <em>p53</em> loss recapitulates the histology and transcriptome of human malignant peripheral nerve sheath tumor
AID  - 10.1101/2021.05.03.442481
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.03.442481
4099  - http://biorxiv.org/content/early/2021/05/04/2021.05.03.442481.short
4100  - http://biorxiv.org/content/early/2021/05/04/2021.05.03.442481.full
AB  - Background Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas. Somatic inactivation of NF1 and cooperating tumor suppressors, including CDKN2A/B, PRC2, and p53, is found in most MPNST. Inactivation of the LATS1/2 kinases of the Hippo pathway was recently shown to cause tumors resembling MPNST histologically, although Hippo pathway mutations are rarely found in MPNST. Because existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST, we aimed to establish a mouse MPNST model that recapitulated the human disease genetically, histologically, and molecularly.Methods We combined two genetically modified alleles, an Nf1;Trp53 cis-conditional allele and an inducible Plp-CreER allele (NP-Plp), to model the somatic, possibly postnatal, mutational events in human MPNST. We also generated conditional Lats1;Lats2 knockout mice. We performed histopathologic analysis of mouse MPNST models and transcriptomic comparison of mouse models and human nerve sheath tumors.Results Postnatal Nf1;Trp53 cis-deletion resulted in GEM-MPNST that was histologically more similar to human MPNST than the widely used germline Nf1;Trp53 cis-heterozygous (NPcis) model and showed partial loss of H3K27me3. At the transcriptome level, Nf1;p53-driven GEM-MPNST were distinct from Lats-driven GEM-MPNST and resembled human MPNST more closely than do Lats-driven tumors.Conclusions The NP-Plp model recapitulates human MPNST genetically, histologically, and molecularly.Key PointsPostnatal Nf1;p53 cis-deletion in NP-Plp mice results in tumors similar to MPNST.The transcriptomes of Nf1;p53-driven and Lats-driven MPNST models are distinct.NP-Plp model resembles human MPNST genetically, histologically, and molecularly.Importance of the Study Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with a poor prognosis and limited treatment options. Existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST. To model the somatic, possibly postnatal, mutational events seen in MPNST patients, we generated a GEM-MPNST model by combining two genetically modified alleles, an Nf1;Trp53 cis-conditional allele and a Plp-CreER allele. Our histologic and transcriptomic analyses showed that this NP-Plp model resembles human MPNST genetically, histologically, and molecularly—more so than the widely used NPcis model and the recently published Lats-driven model. The NP-Plp model is genetically simple, making it easy to maintain and an ideal platform for preclinical studies. Given its tamoxifen-inducible nature, this model can be used to study the time/stage dependency of the tumorigenic potential of Schwann cells.Competing Interest StatementThe authors have declared no competing interest.