title: Concise review: managing genotoxicity in the therapeutic modification of stem cells.
abstract: The therapeutic use of procedures for genetic stem cell modification is limited by potential adverse events related to uncontrolled mutagenesis. Prominent findings have been made in hematopoietic gene therapy, demonstrating the risk of clonal, potentially malignant outgrowth on the basis of mutations acquired during or after therapeutic genome modification. The incidence and the growth rate of insertional mutants have been linked to the "stemness" of the target cells and vector-related features such as the integration pattern, the architecture, and the exact content of transgene cassettes. Milieu factors supporting the survival and expansion of mutants may eventually allow oncogenic progression. Similar concerns apply for medicinal products based on pluripotent stem cells. Focusing on the genetic stress induced by insertional mutagenesis and culture adaptation, we propose four conclusions. (a) Mutations occurring in the production of stem cell-based medicines may be unavoidable and need to be classified according to their risk to trigger the formation of clones that are sufficiently long-lived and mitotically active to acquire secondary transforming mutations. (b) The development of rational prevention strategies depends upon the identification of the specific mutations forming such "dominant clones" (which can also be addressed as cancer stem cell precursors) and a better knowledge of the mechanisms underlying their creation, expansion, and homeostatic control. (c) Quantitative assay systems are required to assess the practical value of preventive actions. (d) Improved approaches for the genetic modification of stem cells can address all critical steps in the origin and growth control of mutants.
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. baum.christopher@mh-hannover.de
authors: Christopher
authors: C
authors: Baum
authors: Ute
authors: U
authors: Modlich
authors: Gudrun
authors: G
authors: Göhring
authors: Brigitte
authors: B
authors: Schlegelberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D016254:Mutagenesis, Insertional; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors