Phenotypic correction of Fanconi anemia group C knockout mice

Kimberly A. Gush, Kai Ling Fu, Markus Grompe, Christopher E. Walsh

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital anomalies, and a predisposition to malignancy. FA cells demonstrate hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). Mice with a targeted disruption of the FANCC gene (fancc -/- nullizygous mice) exhibit many of the characteristic features of FA and provide a valuable tool for testing novel therapeutic strategies. We have exploited the inherent hypersensitivity of fancc -/- hematopoietic cells to assay for phenotypic correction following transfer of the FANCC complementary DNA (cDNA) into bone marrow cells. Murine fancc -/- bone marrow cells were transduced with the use of retrovirus carrying the human fancc cDNA and injected into lethally irradiated recipients. Mitomycin C (MMC) dosing, known to induce pancytopenia, was used to challenge the transplanted animals. Phenotypic correction was determined by assessment of peripheral blood counts. Mice that received cells transduced with virus carrying the wild-type gene maintained normal blood counts following MMC administration. All nullizygous control animals receiving MMC exhibited pancytopenia shortly before death. Clonogenic assay and polymerase chain reaction analysis confirmed gene transfer of progenitor cells. These results indicate that selective pressure promotes in vivo enrichment of fancc-transduced hematopoietic stem/progenitor cells. In addition, MMC resistance coupled with detection of the transgene in secondary recipients suggests transduction and phenotypic correction of long-term repopulating stem cells.

Original languageEnglish (US)
Pages (from-to)700-704
Number of pages5
JournalBlood
Volume95
Issue number2
StatePublished - Jan 15 2000

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Fanconi Anemia
Mitomycin
Knockout Mice
Bone
Pancytopenia
Hematopoietic Stem Cells
Stem cells
Bone Marrow Cells
Assays
Hypersensitivity
Animals
Blood
Stem Cells
Complementary DNA
Genes
Cells
Gene transfer
Inborn Genetic Diseases
Polymerase chain reaction
Retroviridae

ASJC Scopus subject areas

  • Hematology

Cite this

Gush, K. A., Fu, K. L., Grompe, M., & Walsh, C. E. (2000). Phenotypic correction of Fanconi anemia group C knockout mice. Blood, 95(2), 700-704.

Phenotypic correction of Fanconi anemia group C knockout mice. / Gush, Kimberly A.; Fu, Kai Ling; Grompe, Markus; Walsh, Christopher E.

In: Blood, Vol. 95, No. 2, 15.01.2000, p. 700-704.

Research output: Contribution to journalArticle

Gush, KA, Fu, KL, Grompe, M & Walsh, CE 2000, 'Phenotypic correction of Fanconi anemia group C knockout mice', Blood, vol. 95, no. 2, pp. 700-704.
Gush KA, Fu KL, Grompe M, Walsh CE. Phenotypic correction of Fanconi anemia group C knockout mice. Blood. 2000 Jan 15;95(2):700-704.
Gush, Kimberly A. ; Fu, Kai Ling ; Grompe, Markus ; Walsh, Christopher E. / Phenotypic correction of Fanconi anemia group C knockout mice. In: Blood. 2000 ; Vol. 95, No. 2. pp. 700-704.
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