Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution

Laura Haneline, Xiaxin Li, Samantha L M Ciccone, Ping Hong, Yanzhu Yang, Hal Broxmeyer, Suk-Hee Lee, Attilio Orazi, Edward Srour, D. Clapp

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc-/- mice to show that Fancc-/- hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc-/- HSC to wild-type levels. Fancc-/- HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, ∼30% of primary recipients (7 of 22) transplanted with uncorrected Fancc-/- cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc-/- cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-γ, TNF-α, and MIP-1α compared to both Fancc-/- progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc-/- HSCs.

Original languageEnglish
Pages (from-to)1299-1307
Number of pages9
JournalBlood
Volume101
Issue number4
DOIs
StatePublished - Feb 15 2003

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Clonal Evolution
Hematopoietic Stem Cells
Stem cells
Gene transfer
Fanconi Anemia
Retroviridae
Bone
Bone Marrow
Chromosome Disorders
Genes
Chromosomal Instability
Defects
Pancytopenia
Myeloid Leukemia
Clinical Trials
Cytokines
Safety
Incidence

ASJC Scopus subject areas

  • Hematology

Cite this

Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution. / Haneline, Laura; Li, Xiaxin; Ciccone, Samantha L M; Hong, Ping; Yang, Yanzhu; Broxmeyer, Hal; Lee, Suk-Hee; Orazi, Attilio; Srour, Edward; Clapp, D.

In: Blood, Vol. 101, No. 4, 15.02.2003, p. 1299-1307.

Research output: Contribution to journalArticle

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abstract = "Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc-/- mice to show that Fancc-/- hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc-/- HSC to wild-type levels. Fancc-/- HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, ∼30{\%} of primary recipients (7 of 22) transplanted with uncorrected Fancc-/- cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc-/- cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-γ, TNF-α, and MIP-1α compared to both Fancc-/- progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc-/- HSCs.",
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AU - Hong, Ping

AU - Yang, Yanzhu

AU - Broxmeyer, Hal

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AU - Srour, Edward

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N2 - Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc-/- mice to show that Fancc-/- hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc-/- HSC to wild-type levels. Fancc-/- HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, ∼30% of primary recipients (7 of 22) transplanted with uncorrected Fancc-/- cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc-/- cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-γ, TNF-α, and MIP-1α compared to both Fancc-/- progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc-/- HSCs.

AB - Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc-/- mice to show that Fancc-/- hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc-/- HSC to wild-type levels. Fancc-/- HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, ∼30% of primary recipients (7 of 22) transplanted with uncorrected Fancc-/- cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc-/- cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-γ, TNF-α, and MIP-1α compared to both Fancc-/- progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc-/- HSCs.

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