In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1

Paula Río, Néstor W. Meza, África González-Murillo, Susana Navarro, Lara Álvarez, Jordi Surrallés, Maria Castella, Guillermo Guenechea, José C. Segovia, Helmut Hanenberg, Juan A. Bueren

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Fanconi anemia (FA) is an inherited recessive DNA repair disorder mainly characterized by bone marrow failure and cancer predisposition. Studies in mosaic FA patients have shown that reversion of one inherited germ-line mutation resulting in a functional allele in one or a few hemato-poietic stem cells (HSCs) can lead to the proliferation advantage of corrected cells, thus over time normalizing the hemato-logic status of the patient. In contrast to these observations, it is still unclear whether ex vivo genetic correction of FA HSCs also provides a similar proliferation advantage to FA HSCs. Using an FA mouse model with a marked hematopoietic phenotype, the FA-D1 (Brca Δ27/Δ27) mice, we demonstrate that the lentivirus-mediated gene therapy of FA HSCs results in the progressive expansion of genetically corrected clones in mild-conditioned FA-D1 recipients. Consistent with these data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted. No evidence of myelodysplasia, leukemias, or abnormal clonal repopulation was observed at multiple time points in primary or secondary recipients. Our results demonstrate that ectopic expression of BRCA2 confers a beneficial in vivo proliferation advantage to FA-D1 HSCs that enables the full hematopoietic repopula-tion of FA recipients with genetically corrected cells.

Original languageEnglish
Pages (from-to)4853-4861
Number of pages9
JournalBlood
Volume112
Issue number13
DOIs
StatePublished - Dec 15 2008

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Fanconi Anemia
Hematopoietic Stem Cells
Stem cells
Stem Cells
Gene therapy
Mitomycin
Bone
Repair
Bone Neoplasms
Lentivirus
Chromosomal Instability
DNA
Germ-Line Mutation
DNA Repair
Genetic Therapy
Leukemia
Clone Cells
Bone Marrow
Alleles

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Río, P., Meza, N. W., González-Murillo, Á., Navarro, S., Álvarez, L., Surrallés, J., ... Bueren, J. A. (2008). In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1. Blood, 112(13), 4853-4861. https://doi.org/10.1182/blood-2008-05-156356

In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1. / Río, Paula; Meza, Néstor W.; González-Murillo, África; Navarro, Susana; Álvarez, Lara; Surrallés, Jordi; Castella, Maria; Guenechea, Guillermo; Segovia, José C.; Hanenberg, Helmut; Bueren, Juan A.

In: Blood, Vol. 112, No. 13, 15.12.2008, p. 4853-4861.

Research output: Contribution to journalArticle

Río, P, Meza, NW, González-Murillo, Á, Navarro, S, Álvarez, L, Surrallés, J, Castella, M, Guenechea, G, Segovia, JC, Hanenberg, H & Bueren, JA 2008, 'In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1', Blood, vol. 112, no. 13, pp. 4853-4861. https://doi.org/10.1182/blood-2008-05-156356
Río P, Meza NW, González-Murillo Á, Navarro S, Álvarez L, Surrallés J et al. In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1. Blood. 2008 Dec 15;112(13):4853-4861. https://doi.org/10.1182/blood-2008-05-156356
Río, Paula ; Meza, Néstor W. ; González-Murillo, África ; Navarro, Susana ; Álvarez, Lara ; Surrallés, Jordi ; Castella, Maria ; Guenechea, Guillermo ; Segovia, José C. ; Hanenberg, Helmut ; Bueren, Juan A. / In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1. In: Blood. 2008 ; Vol. 112, No. 13. pp. 4853-4861.
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