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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-02-0478.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2575-2583
HEMATOPOIESIS
Bcl-XL is required for heme synthesis during the
chemical induction of erythroid differentiation of murine
erythroleukemia cells independently of its antiapoptotic
function
Khalid Hafid-Medheb,
Yvette Augery-Bourget,
Marie-Nathalie Minatchy,
Nicole Hanania, and
Jacqueline Robert-Lézénès
From INSERM U268-Hôpital Paul-Brousse, Villejuif,
France.
Bcl-XL is essential for the survival and normal
maturation of erythroid cells, especially at the late stage of
erythroid differentiation. It remains unclear whether
Bcl-XL serves only as a survival factor for erythroid cells
or if it can induce a signal for differentiation. We have previously
shown that dimethyl sulfoxide (DMSO) induction of erythroid
differentiation in murine erythroleukemia (MEL) cells correlates with
delay of apoptosis and specific induction of Bcl-XL. In
this study, we investigate the contribution of Bcl-2 and
Bcl-XL to survival and erythroid differentiation by
generating stable MEL transfectants expressing these antiapoptotic
regulators. Overexpression of Bcl-2 completely prevented
apoptosis of MEL cells before and after DMSO induction, whereas
overexpression of Bcl-XL only delayed it. Overexpression of
Bcl-2 or Bcl-XL neither induced spontaneous erythroid
differentiation nor accelerated DMSO-induced differentiation. Inhibition of Bcl-XL by antisense transcripts accelerated
apoptosis in DMSO-treated MEL cells and blocked the synthesis of
hemoglobin without altering the growth arrest associated with terminal
erythroid differentiation. An antisense oligonucleotide to
Bcl-XL did not induce apoptosis in MEL cells overexpressing
Bcl-2 but greatly decreased their hemoglobin synthesis when treated
with DMSO, suggesting that Bcl-XL is necessary for
erythroid differentiation independently of its antiapoptotic function.
Importantly, Bcl-XL antisense transcripts prevented heme
synthesis but not globin mRNA induction in DMSO-treated MEL cells.
Furthermore, inhibition of hemoglobin synthesis by Bcl-XL
antisense was reversed by addition of exogenous hemin. Finally,
Bcl-XL localized to mitochondria during MEL erythroid differentiation, suggesting that it may mediate a critical
mitochondrial transport function related to heme biosynthesis.
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