Tumor cells escape suicide gene therapy by genetic and epigenetic instability

Frank, Oliver; Rudolph, Cornelia; Heberlein, Christoph; Neuhoff, Nils von; Schröck, Evelin; Schambach, Axel; Schlegelberger, Brigitte; Fehse, Boris; Ostertag, Wolfram; Stocking, Carol; Baum, Christopher

doi:10.1182/blood-2004-03-0852

Cited by 55 publications

(43 citation statements)

References 28 publications

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“…S3E). We further investigated chromosomal aberration in the AIMP3 +/À stable cell lines using SKY analysis as previously described (11). Chromosome deletion, duplication, and unbalanced translocations were found in various chromosomes in Ras-or Myc-transformed AIMP3 +/À cells (see Supplementary Table S1 and Fig.…”

Section: Resultsmentioning

confidence: 99%

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AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability

Park

et al. 2006

Cancer Research

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AIMP3 (previously known as p18) was shown to up-regulate p53 in response to DNA damage. Here, we show that AIMP3 couples oncogenic stresses to p53 activation to prevent cell transformation. Growth factor-or Ras-dependent induction of p53 was blocked by single allelic loss of AIMP3 as well as by suppression of AIMP3. AIMP3 heterozygous cells became susceptible to cell transformation induced by oncogenes such as Ras or Myc alone. The transformed AIMP3 +/À cells showed severe abnormality in cell division and chromosomal structure. Thus, AIMP3 plays crucial roles in p53-mediated tumor-suppressive response against oncogenic stresses via differential activation of ATM and ATR, and in the maintenance of genomic stability. (Cancer Res 2006; 66(14): 6913-8)

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Section: Resultsmentioning

confidence: 99%

“…Cytogenetic characterization using spectral karyotyping (SKY) was carried out as previously described (11). In brief, metaphase spreads were hybridized with the SKY probe mixture for mouse chromosomes and signal detection was done according to the manufacturer's instructions (Applied Spectral Imaging, Migdal HaEmek, Israel).…”

Section: Methodsmentioning

confidence: 99%

AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability

Park

et al. 2006

Cancer Research

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“…MLV was also occasionally detectable in our water controls. Cloning by ligation-mediated PCR (8,42) and sequencing of the MLV-related amplicons revealed that MLV RT expression vector molecules occurred in our assay. These have been introduced by the use of a commercial MLV RT (Invitrogen Inc., Carlsbad, CA) for cDNA synthesis that was produced by recombinant bacteria.…”

Section: Resultsmentioning

confidence: 99%

Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders

Frank

Giehl

Zheng

et al. 2005

J Virol

151

163

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The detection and identification of retroviral transcripts in brain samples, cerebrospinal fluid, and plasma of individuals with recent-onset schizophrenia and schizoaffective disorders suggest that activation or upregulation of distinct human endogenous retroviruses (HERVs) may play a role in the etiopathogenesis of neuropsychiatric diseases. To test this hypothesis, we performed a comprehensive microarray-based analysis of HERV transcriptional activity in human brains. We investigated 50 representative members of 20 HERV families in a total of 215 brain samples derived from individuals with schizophrenia or bipolar disorders and matched controls. A characteristic brain-specific retroviral activity profile was found that consists of members of the class I families HERV-E, HERV-F, and ERV9 and members of HERV-K taxa. In addition to these constitutively expressed HERVs, a number of differentially active HERV elements were identified in all brain samples independent of the disease pattern that may reflect differences in the genetic background of the tested individuals. Only a subgroup of the HML-2 family (HERV-K10) was significantly overrepresented in both bipolar-disorder-and schizophrenia-associated samples compared to healthy brains, suggesting a potential association with disease. Real-time PCR analysis of HERV env transcripts with coding capacity potentially involved in neuroinflammatory conditions revealed that env expression of HERV-W, HERV-FRD, and HML-2 remains unaffected regardless of the clinical picture. Our data suggest that HERV transcription in brains is weakly correlated with schizophrenia and related diseases but may be influenced by the individual genetic background, brain-infiltrating immune cells, or medical treatment.

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“…However, long-term benefit was compromised by vector inactivation, resulting in a lack of microbicidal activity in gene-transduced phagocytic cells. Although vector inactivation has been reported in cell lines, embryonic and mouse hematopoietic stem cells 27,28 , methylation of the vector promoter has not been reported in clinical studies so far. In other immunodeficiencies, powerful positive-selection pressures may have obscured this phenomenon, as nonexpressing progenitors would not support further survival and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

Stein

Ott

Schultze-Strasser

et al. 2010

Nat Med

731

562

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Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia. 1 Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany. 2 Department of Hematology/Oncology, University Medical School, Frankfurt, Germany. 3 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 4 Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany. 5 University Women's Clinic, Division Molecular Biology of Breast Cancer, Heidelberg, Germany. 6 Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany. 7 Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. 7 Pediatric Hematology, Oncology and Hemostaseology, University Medical School, Frankfurt, Germany. 8 Department of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 9 Department of Hematology, Oncology and Transfusion Medicine, Charité, Campus Benjamin Franklin, Berlin, Germany. 10 Institute of Pathology, Heinrich-Heine University, Düsseldorf, Germany. 11 EUFETS AG, Idar-Oberstein, Germany. 12 Centre for Immunodeficiency, UCL Institute of Child Health, and Great Ormond Street Hospital for Children NHS Trust London, UK. 13 Division of Immunology/Hematology, University Children's Hospital Zurich, Zurich, Switzerland. 15 These authors contributed equally to this work. a r t i c l e sThe subject received daily granulocyte colonystimulating factor (G-CSF) support (5 µg per kg body weight per day) from months 18 to 20 and months 24 to 26, as well as multiple red blood and platelet transfusions. Following a dental abscess and a febrile episode requiring antibiotic and antimycotic treatment, subject 1 was noted to have extensive splenomegaly and underwent splenectomy at month 25 to avoid spontaneous rupture. Histopathological examination of the spleen revealed extramedullary hematopoiesis and siderosis in the red pulp, without signs of dys...

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Tumor cells escape suicide gene therapy by genetic and epigenetic instability

Cited by 55 publications

References 28 publications

AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability

AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability

Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

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