David H Gutmann

Washington University in St. Louis, San Luis, Missouri, United States

Are you David H Gutmann?

Claim your profile

Publications (460)2776.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that arise sporadically or in association with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. In individuals with NF1, MPNSTs are hypothesized to arise from Nf1-deficient Schwann cell precursor cells following the somatic acquisition of secondary cooperating genetic mutations (e.g., p53 loss). To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains. Using this approach, ~60% of mice with Periostin-Cre-mediated Nf1 gene inactivation (Periostin-Cre; Nf1flox/flox mice) developed tumors classified as low-grade MPNSTs following p53 knockdown (mean, 6 months). Similarly, ~70% of Nf1+/- mice with GFAP-Cre-mediated Nf1 gene inactivation (GFAP-Cre; Nf1flox/null mice) developed low-grade MPNSTs following p53 knockdown (mean, 3 months). In addition, wild-type and Nf1+/- mice with GFAP-Cre-mediated Nf1 loss develop MPNSTs following somatic p53 knockout with different latencies, suggesting potential influences of Nf1+/- stromal cells in MPNST pathogenesis. Collectively, this new MPNST model system permits the analysis of somatically-acquired events as well as tumor microenvironment signals that potentially cooperate with Nf1 loss in the development and progression of this deadly malignancy.
    No preview · Article · Feb 2016 · Oncotarget
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fifteen to 20% of children with neurofibromatosis type 1 develop low-grade glial neoplasms. However, since neuroimaging is not routinely obtained until a child is clinically symptomatic, little is known about presymptomatic radiographic characteristics of gliomas in this at-risk population. Herein, we describe a child with neurofibromatosis type 1 who initially had normal brain imaging before the development of multifocal gliomas. Comparison of these serial images demonstrated that brain tumors can arise de novo in children with this cancer predisposition syndrome, further underscoring the limited prognostic value of normal baseline magnetic resonance imaging.
    No preview · Article · Feb 2016 · Radiology Case Reports
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
    Full-text · Article · Jan 2016 · Cell
  • Jacqueline L. Anderson · David H. Gutmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1), previously known as von Recklinghausen disease, is a neurogenetic disorder distinct from neurofibromatosis type 2 (NF2). Approximately 1:2500 to 1:3500 individuals worldwide are affected, regardless of ethnicity or race. The classic manifestations of NF1 include café-au-lait macules, skinfold freckling, neurofibromas, brain tumors, iris hamartomas, and characteristic bony lesions. In addition, patients with NF1 are at increased risk for learning and intellectual disabilities, aqueductal stenosis, pheochromocytoma, vascular dysplasia, scoliosis, and cancer. In this chapter, we discuss the clinical and molecular features of NF1 as well as how insights into its underlying molecular pathophysiology have revealed new targets for therapeutic drug design.
    No preview · Chapter · Dec 2015
  • Adam P. Ostendorf · David H. Gutmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) and type 2 (NF2) are autosomal dominant tumor predisposition syndromes with prominent involvement of the central and peripheral nervous systems. Clinical features of NF1 typically include, but are not limited to, café-au-lait spots, neurofibromas, skinfold freckling, optic pathway gliomas, Lisch nodules and bony lesions, such as sphenoid bone dysplasia. Neurofibromatosis type 2 is characterized by the development of bilateral vestibular schwannomas, meningiomas, ependymomas, and lenticular opacities. Both syndromes result from mutations in tumor suppressor genes, whose loss of function leads to increased cell growth. Molecular biology and animal models have provided critical new insights into the mechanisms underlying NF1 and NF2 protein function. While past treatment approaches have been focused on traditional chemotherapy or surgical techniques, the improved understanding of the pathogenesis of these conditions afforded by basic science research has led to the implementation of novel targeted therapies.
    No preview · Chapter · Dec 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.
    No preview · Article · Dec 2015 · Nature Neuroscience
  • Suzanne J. Baker · David W. Ellison · David H. Gutmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults. GLIA 2015.
    No preview · Article · Dec 2015 · Glia

  • No preview · Article · Nov 2015 · Neuro-Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with Neurofibromatosis type 1 (NF1) are at increased risk for pediatric brain tumors (PBTs), especially optic gliomas; however, factors influencing their development are largely unknown. Extensive research suggests that allergic conditions protect against brain tumors, particularly gliomas in individuals without NF1. In this large cross-sectional study, we employed two different data sources to evaluate evidence for the hypothesis that allergic conditions (allergies, asthma, and eczema) may protect against PBT development in individuals with NF1. We used self- and parent/legal guardian reported questionnaire data from participants in the NF1 Patient Registry Initiative (NPRI, n = 1660) born from 1933 to 2014 to ascertain allergic condition and PBT diagnosis histories. Medical records (MRs) of 629 NF1 patients at a large medical center born from 1930 to 2012 were also reviewed for PBT and allergic condition diagnoses to evaluate additional evidence for our hypothesis. We used logistic regression to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between allergic condition diagnoses and PBTs. Both data sources provided limited to no support for a protective effect of allergies or eczema on PBT development. Non-significant inverse associations between asthma and PBTs were observed (NPRI: OR = 0.80, 95 % CI 0.55-1.17; MR: OR = 0.71, 95 % CI 0.40-1.28) with stronger associations for optic gliomas specifically. Additionally, a significant inverse association was observed in an NPRI subgroup analysis where the reported asthma diagnosis age was younger than the reported PBT diagnosis age (OR = 0.57; 95 % CI 0.36-0.89). Our study supports the hypothesis that asthma protects against PBT development in NF1.
    Preview · Article · Nov 2015 · Neuro-Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.
    Preview · Article · Oct 2015 · Neoplasia (New York, N.Y.)
  • Source
    Yi-Hsien Chen · Scott M Gianino · David H Gutmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation. Collectively, these findings establish distinct roles for the RAS effector pathways in regulating brain NSC function. © 2015 Chen et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Aug 2015 · Genes & development
  • Source

    Full-text · Dataset · Jul 2015
  • Source

    Full-text · Dataset · Jun 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · The Journal of pediatrics
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate evidence for differences in pediatric brain tumor diagnoses by race and ethnicity using a cross-sectional study design in individuals with neurofibromatosis type 1 (NF1). Subjects with NF1 were ascertained from the NF1 Patient Registry Initiative and through a clinical record database of patients at a large academic medical center. Logistic regression was employed to calculate ORs and 95% CIs to analyze differences in the odds of brain tumor diagnosis by race (White, Black, Asian, other/unknown) and ethnic (Hispanic vs non-Hispanic) groups. Data from a total of 1546, 629, and 2038 individuals who were ascertained from the NF1 Patient Registry Initiative, clinical records, and pooled datasets were analyzed, respectively. After adjusting for birth year, we observed a significantly reduced odds of brain tumor diagnoses in individuals self-identified or clinically reported as Black (OR = 0.13, 95% CI 0.05-0.31), Asian (OR = 0.15, 95% CI 0.04-0.64), and other/unknown (OR = 0.61, 95% CI 0.41-0.93) race compared with those with reported as White race. There was no significant difference in the odds of pediatric brain tumor diagnosis by Hispanic ethnicity. Consistent with prior smaller studies, these data suggest that pediatric brain tumor diagnoses vary by race in individuals with NF1. Reasons underlying observed differences by race warrant further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · The Journal of pediatrics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have employed a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. Whole exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n=3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was employed for functional analysis. There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with non-synonymous somatic mutations (beta III-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Lastly, increased beta III-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Apr 2015 · Clinical Cancer Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.Molecular Psychiatry advance online publication, 28 April 2015; doi:10.1038/mp.2015.48.
    Full-text · Article · Apr 2015 · Molecular Psychiatry
  • R Hugh · F Bender · Kevin M Haigis · David H Gutmann
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since some neurodevelopmental brain disorders (Costello syndrome, Noonan syndrome) are caused by germline activating mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional activated Ras molecule-expressing genetically-engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a non-canonical mechanism. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    No preview · Article · Mar 2015 · Stem Cells
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells (iPSCs) and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cAMP generation, there was a neurofibromin dose-dependent reduction in dopamine levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse (GEM) strains in which hippocampal-based learning and memory is dopamine-dependent to establish that neuronal dopamine levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Mar 2015 · Human Molecular Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cell Reports

Publication Stats

19k Citations
2,776.08 Total Impact Points


  • 1994-2015
    • Washington University in St. Louis
      • • Department of Neurology
      • • Department of Medicine
      • • Department of Pediatrics
      San Luis, Missouri, United States
  • 2014
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2005-2014
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Neuropathology
      Magdeburg, Saxony-Anhalt, Germany
  • 2013
    • Guy's and St Thomas' NHS Foundation Trust
      • Department of Neurology
      Londinium, England, United Kingdom
  • 2008
    • Saint Louis University
      Сент-Луис, Michigan, United States
  • 2007
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, Georgia, United States
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
  • 1997-2007
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 2006
    • University of California, San Francisco
      • Department of Pediatrics
      San Francisco, California, United States
  • 2004
    • University of Texas at Dallas
      Richardson, Texas, United States
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 1996-2003
    • University of Toronto
      • Division of Neurosurgery
      Toronto, Ontario, Canada
    • University of Groningen
      • Department of Neurosurgery
      Groningen, Groningen, Netherlands
  • 2002
    • King's College London
      • Department of Clinical Neuroscience
      Londinium, England, United Kingdom
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • Children's National Medical Center
      • Department of Neurology
      Washington, Washington, D.C., United States
  • 2001
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • Children's Memorial Hospital
      Chicago, Illinois, United States
    • University of Washington Seattle
      Seattle, Washington, United States
    • University of Pennsylvania
      • Department of Neurology
      Filadelfia, Pennsylvania, United States
  • 1999
    • University of Iowa
      Iowa City, Iowa, United States
  • 1991-1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1992-1993
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
  • 1990-1992
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States