title: Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy.
abstract: Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Deichmann
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Brugman
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Bartholomae
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarzwaelder
authors.forename: Monique M A
authors.initials: MM
authors.lastname: Verstegen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Anne
authors.initials: A
authors.lastname: Arens
authors.forename: Marion G
authors.initials: MG
authors.lastname: Ott
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seger
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anna
authors.initials: A
authors.lastname: Paruzynski
authors.forename: Richard
authors.initials: R
authors.lastname: Gabriel
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abel
authors.forename: Claudia
authors.initials: C
authors.lastname: Cattoglio
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Gerard
authors.initials: G
authors.lastname: Wagemaker
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D017988:Gammaretrovirus / Q000235:genetics*; D053263:Gene Regulatory Networks; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects*; D016678:Genome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D011323:Primates; D019737:Transplants; D016662:Virus Integration; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000628:therapy