Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy

Annette Deichmann, Martijn H. Brugman, Cynthia C. Bartholomae, Kerstin Schwarzwaelder, Monique M A Verstegen, Steven J. Howe, Anne Arens, Marion G. Ott, Dieter Hoelzer, Reinhard Seger, Manuel Grez, Salima Hacein-Bey-Abina, Marina Cavazzana-Calvo, Alain Fischer, Anna Paruzynski, Richard Gabriel, Hanno Glimm, Ulrich Abel, Claudia Cattoglio, Fulvio MavilioBarbara Cassani, Alessandro Aiuti, Cynthia E. Dunbar, Christopher Baum, H. Bobby Gaspar, Adrian J. Thrasher, Christof Von Kalle, Manfred Schmidt, Gerard Wagemaker

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2031-2039
Number of pages9
JournalMolecular Therapy
Volume19
Issue number11
DOIs
Publication statusPublished - Nov 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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