Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient
Date Published: February 17, 2009
Publisher: Public Library of Science
Author(s): Ninette Amariglio, Abraham Hirshberg, Bernd W Scheithauer, Yoram Cohen, Ron Loewenthal, Luba Trakhtenbrot, Nurit Paz, Maya Koren-Michowitz, Dalia Waldman, Leonor Leider-Trejo, Amos Toren, Shlomi Constantini, Gideon Rechavi, Alain Fischer
Abstract: Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.
Methods and Findings: A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient’s peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.
Conclusions: This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.
Partial Text: Research in recent years has demonstrated that neurogenesis constitutively occurs in specific regions of the adult mammalian brain and that there are substantial numbers of multipotent stem/precursor cells from many parts of the brain that may be used therapeutically [1–4]. The fetal brain, characterized by active neurogenesis, has been suggested to be a promising source of therapeutic neural stem cells . Neural stem cells are being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma [1–4,6–9]. Such cells have also been suggested as potential therapies for infants and children affected by genetic and acquired diseases characterized by neurological deterioration [1,5].
We describe here a patient with AT who was treated repeatedly with fetal neural stem cells and who developed a multifocal brain tumor. Histology and immune phenotyping of the resected mass led to the diagnosis of a glioneuronal tumor. This is the first report of a human brain tumor developing from transplanted neural stem cells. The results obtained from the various cytogenetic and molecular studies performed on the tumor led us to conclude that the tumor is derived from the neural stem cells obtained from at least two aborted fetuses that were administered a few years earlier. This case therefore confirms that the concerns raised regarding the risk of tumor development resulting from therapeutic transplantation of neural stem/precursor cells were not unfounded.
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