A Comprehensive Overview of NF1 Mutations in Iranian Patients.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.

The genetic spectrum of NF1 variants in 10 unrelated Chinese families with neurofibromatosis type 1.

OBJECTIVES: To investigate the clinical and genetic features in a cohort of Chinese families with neurofibromatosis type 1 (NF1). METHODS: The clinical information of 21 patients with NF1 in 10 families was retrospectively analyzed. To broaden the genetic spectrum of NF1, multiplex ligation-dependent probe amplification analysis was performed first, followed by the whole-exome sequencing, in order to identify pathogenic or potentially pathogenic variants of NF1 gene in 10 unrelated Chinese families. RESULTS: Nine different NF1 variants were identified in all 10 families. Of these, 7 were known pathogenic variants and included the exon 1 deletion, exons 1-58 deletion, c.5401C>T (p.Q1801*), c.2291-2A>C, c.484C>T (p.Q162*), c.4922G>A (p.W1641*) and c.1019_1020del (p.S340Cfs*25). The 2 novel variants were c.5197T>C (p.S1733P) and c.783_797delinsC (p.K261Nfs*25). The p.S1733P variant was classified as a variant of uncertain significance, while p.K261Nfs*25 was classified as pathogenic. Hence, the positive detection rate of NF1 variants was 100% (10/10). While the truncating variants were responsible for 60.0% (6/10) of the cases, the splicing variant was responsible for 10% (1/10) of the cases. CONCLUSION: We identified 2 novel heterozygous variants (c.5197T>C and c.783_797delinsC) in the NF1 gene, which broadens the genetic spectrum of the NF1 gene.

Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes.

NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two "likely pathogenic" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients' follow-up.

Revisiting the NPcis mouse model: A new tool to model plexiform neurofibroma.

Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.

Dietary intervention rescues a bone porosity phenotype in a murine model of Neurofibromatosis Type 1 (NF1).

Neurofibromatosis type 1 (NF1) is a complex genetic disorder that affects a range of tissues including muscle and bone. Recent preclinical and clinical studies have shown that Nf1 deficiency in muscle causes metabolic changes resulting in intramyocellular lipid accumulation and muscle weakness. These can be subsequently rescued by dietary interventions aimed at modulating lipid availability and metabolism. It was speculated that the modified diet may rescue defects in cortical bone as NF1 deficiency has been reported to affect genes involved with lipid metabolism. Bone specimens were analyzed from wild type control mice as well as Nf1Prx1-/- (limb-targeted Nf1 knockout mice) fed standard chow versus a range of modified chows hypothesized to influence lipid metabolism. Mice were fed from 4 weeks to 12 weeks of age. MicroCT analysis was performed on the cortical bone to examine standard parameters (bone volume, tissue mineral density, cortical thickness) and specific porosity measures (closed pores corresponding to osteocyte lacunae, and larger open pores). Nf1Prx1-/- bones were found to have inferior bone properties to wild type bones, with a 4-fold increase in the porosity attributed to open pores. These measures were rescued by dietary interventions including a L-carnitine + medium-chain fatty acid supplemented chow previously shown to improve muscle histology function. Histological staining visualized these changes in bone porosity. These data support the concept that lipid metabolism may have a mechanistic impact on bone porosity and quality in NF1.

An Overview of Optic Pathway Glioma With Neurofibromatosis Type 1: Pathogenesis, Risk Factors, and Therapeutic Strategies.

Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.

snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors.

PURPOSE OF REVIEW: Neurofibromatosis type 1 (NF-1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene that encodes the neurofibromin protein, which functions as a negative regulator of Ras signaling. We review the past, current, and future state of therapeutic strategies for tumors associated with NF-1. RECENT FINDINGS: Therapeutic efforts for NF-1-associated tumors have centered around inhibiting Ras output, leading to the clinical success of downstream MEK inhibition for plexiform neurofibromas and low-grade gliomas. However, MEK inhibition and similar molecular monotherapy approaches that block Ras signaling do not work for all patients and show limited efficacy for more aggressive cancers such as malignant peripheral nerve sheath tumors and high-grade gliomas, motivating novel treatment approaches. We highlight the current therapeutic landscape for NF-1-associated tumors, broadly categorizing treatment into past strategies for serial Ras pathway blockade, current approaches targeting parallel oncogenic and tumor suppressor pathways, and future avenues of investigation leveraging biologic and technical innovations in immunotherapy, pharmacology, and gene delivery.

Generation of a human iPSC line CIPi004-A from a patient with neurofibromatosis type 1 and epilepsy harboring a heterozygous mutation in NF1 gene.

The NF1 gene is related to neurofibromatosis type 1 (NF1), which is an autosomal dominant disorder associated with multisystem involvement and epilepsy susceptibility. A human induced pluripotent stem cell (iPSC) line was derived from a pediatric patient with NF1 and epilepsy, harboring a heterozygous NF1 gene mutation. The iPSC line exhibits high levels of pluripotency markers, maintains the NF1 gene mutation, and demonstrates the capacity to undergo differentiation potential in vitro into three germ layers. The iPSC line will serve as a valuable resource for investigating the underlying mechanisms and conducting drug screening related to NF1 and NF1-associated epilepsy.

Recurrent spontaneous pneumothorax in an NF1 patient with a novel causative variant: broadening genotype-phenotype correlations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance, most commonly known to affect the skin and eyes. Although lung involvement in the form of cysts and bullae occurs in up to 20% of adults, the seemingly intuitive association of NF1 and spontaneous pneumothorax is not widely recognised among clinicians. Here, we report the second case of recurring spontaneous pneumothorax in the context of NF1 with a confirmed molecular diagnosis. In both cases, the NF1 variants featured a premature stop codon in the C-terminal protein domain. Interestingly, our patient had mild skin symptoms, suggesting that spontaneous pneumothorax may not be correlated with cutaneous disease severity. More genotype-phenotype correlation studies are needed for NF1 in general and for its link to spontaneous pneumothorax in particular.

Drosophila Contributions towards Understanding Neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

Autism spectrum disorder profiles in RASopathies: A systematic review.

BACKGROUND: RASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually. METHODS: We conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers. RESULTS: We included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies. CONCLUSIONS: Our systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.

Epilepsy in neurofibromatosis type 1: Prevalence, phenotype, and genotype in adults.

PURPOSE: Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood. METHODS: Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model. RESULTS: Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI95%=6-18%) and point prevalence 7% (CI95%= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI95%=3-65) and specificity of 99% (CI95%=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI95%=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI95%=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI95%=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy. CONCLUSIONS: In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.

[Analysis of NF1 gene variants in a Chinese pedigree and a sporadic patient with Neurofibromatosis type 1].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree and a sporadic case with Neurofibromatosis type 1 (NF1). METHODS: Clinical data of the pedigree and the sporadic case were collected. Genomic DNA was extracted from peripheral venous blood samples and subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis. RESULTS: All patients from the pedigree were found to harbor a c.3251delC variant in exon 25 of the NF1 gene, whilst a c.4312_4314delGAA variant was found in exon 32 of the NF1 gene in the sporadic case. CONCLUSION: Variants of the NF1 gene may account for the occurrence of NF1 in this pedigree and sporadic case.

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs.

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.