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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-02-0478.
Submitted February 13, 2002
Accepted November 12, 2002
Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its anti-apoptotic function
Khalid Hafid-Medheb, Yvette Augery-Bourget, Marie-Nathalie Minatchy, Nicole Hanania, and Jacqueline Robert-Lezenes*
Hopital Paul Brousse, INSERM, Unite 268, Villejuif, France
* Corresponding author; email: jrl{at}infobiogen.fr.
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 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 anti-apoptotic 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 anti-apoptotic 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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