In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice

Paula Río, José Carlos Segovia, Helmut Hanenberg, José Antonio Casado, Jesús Martínez, Kerstin Göttsche, Ngan Ching Cheng, Henri J. Van De Vrugt, Fré Arwert, Hans Joenje, Juan A. Bueren

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52 Scopus citations


Fanconi anemia (FA) is a rare autosomal recessive disease, characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors. The hematopoiesis of these animals was characterized by a modest though significant thrombocytopenia, consistent with reduced numbers of BM megakaryocyte progenitors. As observed in other FA models, the hematopoietic progenitors from Fanca-/- mice were highly sensitive to mitomycin C (MMC). In addition, we observed for the first time in a FA mouse model a marked in vitro growth defect of Fanca-/- progenitors, either when total BM or when purified Lin-Sca-1+ cells were subjected to in vitro stimulation. Liquid cultures of Fanca-/- BM that were stimulated with stem cell factor plus interleukin-11 produced low numbers of granulocyte macrophage colony-forming units, contained a high proportion of apoptotic cells, and generated a decreased proportion of granulocyte versus macrophage cells, compared to normal BM cultures. Aiming to correct the phenotype of Fanca-/- progenitors, purified Lin-Sca-1+ cells were transduced with retroviral vectors encoding the enhanced green fluorescent protein (EGFP) gene and human FANCA genes. Lin-Sca-1+ cells from Fanca-/- mice were transduced with an efficiency similar to that of samples from wild-type mice. More significantly, transductions with FANCA vectors corrected both the MMC hypersensitivity as well as the impaired ex vivo expansion ability that characterized the BM progenitors of Fanca-/- mice.

Original languageEnglish (US)
Pages (from-to)2032-2039
Number of pages8
Issue number6
StatePublished - Sep 15 2002

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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