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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 S., Clapp, D. Wade·2005·Blood
DOI 10.1182/blood-2004-06-2483
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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.

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Metadata

Authors
Li, X., Le Beau, M. M., Ciccone, S., Yang, F.-C., Freie, B., Chen, S., Yuan, J., Hong, P., Orazi, A., Haneline, L. S., & Clapp, D. W.
Affiliations
From the Department of Pediatrics, Herman B Wells Center for Pediatric Research, Section of Hematology/Oncology, University of Chicago, Chicago, IL; and the Departments of Microbiology/Immunology and Pathology, Indiana University School of Medicine, Indianapolis, IN.
Venue
Blood
Publisher
American Society of Hematology
Published
2005-05-01
Volume
105
Issue
9
Pages
3465-3471
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2004-06-2483
Cited by
53
References
3
Language
en

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CoChat. (2026). Citation check: 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. https://app.cochat.ai/papers/10.1182/blood-2004-06-2483
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Li, X., Le Beau, M. M., Ciccone, S., Yang, F.-C., Freie, B., Chen, S., Yuan, J., Hong, P., Orazi, A., Haneline, L. S., & Clapp, D. W. (2005). 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. Blood. https://doi.org/10.1182/blood-2004-06-2483