Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy

Xiaxin Li, Michelle M. Le Beau, Samantha Ciccone, Feng Chun Yang, Brian Freie, Shi Chen, Jin Yuan, Ping Hong, Attilio Orazi, Laura Haneline, D. Clapp

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Abstract

Current strategies for genetic therapy using Moloney retroviruses require ex vivo manipulation of hematopoietic cells to facilitate stable integration of the transgene. While many studies have evaluated the impact of ex vivo culture on normal murine and human stem/progenitor cells, the cellular consequences of ex vivo manipulation of stem cells with intrinsic defects in genome stability are incompletely understood. Here we show that ex vivo culture of Fancc -/- bone marrow cells results in a time-dependent increase in apoptosis of primitive Fancc-/- progenitor cells in conditions that promote the proliferation of wild-type stem/progenitor cells. Further, recipients reconstituted with the surviving Fancc-/- cells have a high incidence of cytogenetic abnormalities and myeloid malignancies that are associated with an acquired resistance to tumor necrosis factor α (TNF-α). Collectively, these data indicate that the intrinsic defects in the genomic stability of Fancc-/- stem/progenitor cells provide a selective pressure for cells that are resistant to apoptosis and have a propensity for the evolution to clonal hematopoiesis and malignancy. These studies could have implications for the design of genetic therapies for treatment of Fanconi anemia and potentially other genetic diseases with intrinsic defects in genome stability.

Original languageEnglish
Pages (from-to)3465-3471
Number of pages7
JournalBlood
Volume105
Issue number9
DOIs
StatePublished - May 1 2005

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Stem cells
Cell culture
Chromosome Aberrations
Stem Cells
Apoptosis
Defects
Genomic Instability
Neoplasms
Genes
Genetic Therapy
Bone
Tumor Necrosis Factor-alpha
Cells
Clonal Evolution
Fanconi Anemia
Inborn Genetic Diseases
Hematopoiesis
Retroviridae
Transgenes
Bone Marrow Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy. / Li, Xiaxin; Le Beau, Michelle M.; Ciccone, Samantha; Yang, Feng Chun; Freie, Brian; Chen, Shi; Yuan, Jin; Hong, Ping; Orazi, Attilio; Haneline, Laura; Clapp, D.

In: Blood, Vol. 105, No. 9, 01.05.2005, p. 3465-3471.

Research output: Contribution to journalArticle

Li, Xiaxin ; Le Beau, Michelle M. ; Ciccone, Samantha ; Yang, Feng Chun ; Freie, Brian ; Chen, Shi ; Yuan, Jin ; Hong, Ping ; Orazi, Attilio ; Haneline, Laura ; Clapp, D. / Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy. In: Blood. 2005 ; Vol. 105, No. 9. pp. 3465-3471.
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