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PMID: 17119121 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.

Blood ·Vol. 109 ·No. 5 ·2007-03-01 ·Pages 1897-907

Kustikova OS, Geiger H, Li Z, Brugman MH, Chambers SM, Shaw CA, Pike-Overzet K, de Ridder D, Staal FJ, von Keudell G, Cornils K, Nattamai KJ, Modlich U, Wagemaker G, Goodell MA, Fehse B, Baum C

Abstract

Evidence from model organisms and clinical trials reveals that the random insertion of retrovirus-based vectors in the genome of long-term repopulating hematopoietic cells may increase self-renewal or initiate malignant transformation. Clonal dominance of nonmalignant cells is a particularly interesting phenotype as it may be caused by the dysregulation of genes that affect self-renewal and competitive fitness. We have accumulated 280 retrovirus vector insertion sites (RVISs) from murine long-term studies resulting in benign or malignant clonal dominance. RVISs (22.5%) are located in or near (up to 100 kb [kilobase]) to known proto-oncogenes, 49.6% in signaling genes, and 27.9% in other or unknown genes. The resulting insertional dominance database (IDDb) shows substantial overlaps with the transcriptome of hematopoietic stem/progenitor cells and the retrovirus-tagged cancer gene database (RTCGD). RVISs preferentially marked genes with high expression in hematopoietic stem/progenitor cells, and Gene Ontology revealed an overrepresentation of genes associated with cell-cycle control, apoptosis signaling, and transcriptional regulation, including major "stemness" pathways. The IDDb forms a powerful resource for the identification of genes that stimulate or transform hematopoietic stem/progenitor cells and is an important reference for vector biosafety studies in human gene therapy.

MeSH Terms
Animals Bone Marrow Transplantation Cell Differentiation Cell Line, Tumor Databases, Factual Genetic Vectors/genetics Hematopoiesis Humans Mice Mice, Inbred C57BL Mutation/genetics Polymerase Chain Reaction Probability Retroviridae/genetics Stem Cells/cytology,metabolism Transcription, Genetic/genetics
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Kustikova Olga S
Department of Experimental Hematology, Hannover Medical School, Germany.
Geiger Hartmut
Li Zhixiong
Brugman Martijn H
Chambers Stuart M
Shaw Chad A
Pike-Overzet Karin
de Ridder Dick
Staal Frank J T
von Keudell Gottfried
Cornils Kerstin
Nattamai Kalpana Jekumar
Modlich Ute
Wagemaker Gerard
Goodell Margaret A
Fehse Boris
Baum Christopher
References (56)
56 references, click to expand
  1. Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell.
    Leukemia. 2002 Sep;16(9):1655-63 PMID: 12200677
  2. Genotoxicity of retroviral integration in hematopoietic cells.
    Mol Ther. 2006 Jun;13(6):1031-49 PMID: 16624621
  3. Polyclonal long-term repopulating stem cell clones in a primate model.
    Blood. 2002 Oct 15;100(8):2737-43 PMID: 12351380
  4. A stem cell molecular signature.
    Science. 2002 Oct 18;298(5593):601-4 PMID: 12228721
  5. Rules for making human tumor cells.
    N Engl J Med. 2002 Nov 14;347(20):1593-603 PMID: 12432047
  6. Initial sequencing and comparative analysis of the mouse genome.
    Nature. 2002 Dec 5;420(6915):520-62 PMID: 12466850
  7. High-level ectopic HOXB4 expression confers a profound in vivo competitive growth advantage on human cord blood CD34+ cells, but impairs lymphomyeloid differentiation.
    Blood. 2003 Mar 1;101(5):1759-68 PMID: 12406897
  8. Side effects of retroviral gene transfer into hematopoietic stem cells.
    Blood. 2003 Mar 15;101(6):2099-114 PMID: 12511419
  9. Retroviral insertional mutagenesis: tagging cancer pathways.
    Adv Cancer Res. 2003;88:53-99 PMID: 12665053
  10. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration.
    Nat Biotechnol. 2006 Jun;24(6):687-96 PMID: 16732270
  11. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells.
    EMBO J. 2006 Aug 9;25(15):3515-23 PMID: 16858398
  12. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
    Nature. 2006 Aug 17;442(7104):818-22 PMID: 16862118
  13. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity.
    Blood. 2006 Oct 15;108(8):2545-53 PMID: 16825499
  14. Focus on acute leukemias.
    Cancer Cell. 2002 Jun;1(5):417-20 PMID: 12124171
  15. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells.
    Nat Med. 2000 Jun;6(6):652-8 PMID: 10835681
  16. Homeobox genes in leukemogenesis.
    Int J Hematol. 2000 Jun;71(4):301-8 PMID: 10905048
  17. Detection and direct genomic sequencing of multiple rare unknown flanking DNA in highly complex samples.
    Hum Gene Ther. 2001 May 1;12(7):743-9 PMID: 11339891
  18. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.
    N Engl J Med. 2002 Apr 18;346(16):1185-93 PMID: 11961146
  19. Murine leukemia induced by retroviral gene marking.
    Science. 2002 Apr 19;296(5567):497 PMID: 11964471
  20. T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis.
    Microbiol Mol Biol Rev. 2002 Jun;66(2):179-202 PMID: 12040123
  21. Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice.
    Blood. 2002 Jul 1;100(1):238-45 PMID: 12070033
  22. Bethesda proposals for classification of lymphoid neoplasms in mice.
    Blood. 2002 Jul 1;100(1):246-58 PMID: 12070034
  23. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.
    Science. 2002 Jun 28;296(5577):2410-3 PMID: 12089448
  24. Transcription start regions in the human genome are favored targets for MLV integration.
    Science. 2003 Jun 13;300(5626):1749-51 PMID: 12805549
  25. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.
    Science. 2003 Oct 17;302(5644):415-9 PMID: 14564000
  26. Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population.
    Blood. 2003 Dec 1;102(12):3934-7 PMID: 12881303
  27. RTCGD: retroviral tagged cancer gene database.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D523-7 PMID: 14681473
  28. Wnt target genes identified by DNA microarrays in immature CD34+ thymocytes regulate proliferation and cell adhesion.
    J Immunol. 2004 Jan 15;172(2):1099-108 PMID: 14707084
  29. Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells.
    Blood. 2004 Jun 1;103(11):4126-33 PMID: 14962901
  30. Molecular signatures of proliferation and quiescence in hematopoietic stem cells.
    PLoS Biol. 2004 Oct;2(10):e301 PMID: 15459755
  31. Safety issues related to retroviral-mediated gene transfer in humans.
    Hum Gene Ther. 1991 Spring;2(1):5-14 PMID: 1863639
  32. Mouse hematopoietic stem cells.
    Blood. 1991 Sep 15;78(6):1395-402 PMID: 1884012
  33. Transduction of pluripotent human hematopoietic stem cells demonstrated by clonal analysis after engraftment in immune-deficient mice.
    Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2414-9 PMID: 8637888
  34. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.
    Lancet. 2004 Dec 18-31;364(9452):2181-7 PMID: 15610804
  35. Relationship between retroviral DNA-integration-site selection and host cell transcription.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1436-41 PMID: 15659548
  36. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment.
    Cell. 2005 Apr 22;121(2):295-306 PMID: 15851035
  37. Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis.
    Blood. 2005 Jun 1;105(11):4235-46 PMID: 15713797
  38. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking.
    Science. 2005 May 20;308(5725):1171-4 PMID: 15905401
  39. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling.
    J Exp Med. 2005 Jun 6;201(11):1715-23 PMID: 15928199
  40. Retroviral integration sites correlate with expressed genes in hematopoietic stem cells.
    Stem Cells. 2005 Sep;23(8):1050-8 PMID: 16140869
  41. Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells.
    Blood. 2005 Oct 1;106(7):2530-3 PMID: 15933056
  42. Cooperating cancer-gene identification through oncogenic-retrovirus-induced insertional mutagenesis.
    Blood. 2005 Oct 1;106(7):2498-505 PMID: 15961513
  43. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells.
    Blood. 2005 Dec 1;106(12):3932-9 PMID: 16109773
  44. Retroviral insertional mutagenesis: past, present and future.
    Oncogene. 2005 Nov 21;24(52):7656-72 PMID: 16299527
  45. Hematopoietic stem cells do not engraft with absolute efficiencies.
    Blood. 2006 Jan 15;107(2):501-7 PMID: 16204316
  46. Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR.
    Blood. 2006 Jan 15;107(2):733-41 PMID: 16204320
  47. Significance of murine retroviral mutagenesis for identification of disease genes in human acute myeloid leukemia.
    Cancer Res. 2006 Jan 15;66(2):622-6 PMID: 16423987
  48. Maximum significance clustering of oligonucleotide microarrays.
    Bioinformatics. 2006 Feb 1;22(3):326-31 PMID: 16303800
  49. Foamy virus vector integration sites in normal human cells.
    Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1498-503 PMID: 16428288
  50. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells.
    Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1457-62 PMID: 16432223
  51. EVI1 and hematopoietic disorders: history and perspectives.
    Gene. 2006 Mar 1;368:1-11 PMID: 16314052
  52. Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors.
    Hum Gene Ther. 2006 Mar;17(3):253-63 PMID: 16544975
  53. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.
    Nat Med. 2006 Apr;12(4):401-9 PMID: 16582916
  54. Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque.
    Blood. 2006 May 15;107(10):3865-7 PMID: 16439674
  55. Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells.
    Oncogene. 2006 May 4;25(19):2697-707 PMID: 16407845
  56. HIV-1 integration in the human genome favors active genes and local hotspots.
    Cell. 2002 Aug 23;110(4):521-9 PMID: 12202041
Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-08-044156
Published
2007-03-01
Epub
2006-00-21
Pages
1897-907
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1801061
Subset
IM
Grants
NCI NIH HHS · R01 CA107492 · United States
NCI NIH HHS · R01-CA107492-01A2 · United States
External Links
PubMed source DOI: 10.1182/blood-2006-08-044156 PMC Full Text View journal details
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