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Suppression of apoptosis in hematopoietic factor-dependent progenitor cell
lines by expression of the FAC gene
RC Cumming, JM Liu, H Youssoufian and M Buchwald
Department of Genetics, Research Institute, The Hospital For Sick Children,
Toronto, Ontario, Canada.
Fanconi anemia (FA) is a genetically heterogeneous, inherited blood
disorder characterized by bone marrow failure, congenital malformations,
and a predisposition to leukemias. Because FA cells are hypersensitive to
DNA cross-linking agents and have chromosomal instability, FA has been
viewed as a disorder of DNA repair. However, the exact cellular defect in
FA cells has not been identified. Sequence analysis of the gene defective
in group C patients (FAC) has shown no significant homologies to other
known genes. The FAC protein has been localized to the cytoplasm,
indicating that FAC may either play an indirect role in DNA repair or is
involved in a different cellular pathway. Recent evidence has indicated
that FA cells may be predisposed to apoptosis, especially after treatment
with DNA cross-linking agents. The demonstration that genes can suppress
apoptosis has been accomplished by overexpression of such genes in growth
factor-dependent cell lines that die by apoptosis after factor withdrawal.
Using retroviral-mediated gene transfer, we present evidence that
expression of FAC in the hematopoietic factor-dependent progenitor cell
lines 32D and MO7e can suppress apoptosis induced by growth factor
withdrawal. Flow cytometry and morphologic analysis of propidium iodide
stained cells showed significantly lower levels of apoptosis in
FAC-retroviral transduced cells after growth factor deprivation. Expression
of FAC in both cell lines promoted increased viability rather than
proliferation, which is consistent with other apoptosis-inhibiting genes
such as Bcl- 2. These findings imply that FAC may act as a mediator of an
apoptotic pathway initiated by growth factor withdrawal. Furthermore, the
congenital malformations and hematologic abnormalities characterizing FA
may be related to an increased predisposition of FA progenitor cells to
undergo apoptosis, particularly in the absence of extracellular signals.
Volume 88,
Issue 12,
pp. 4558-4567,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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