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Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum

E Gyan1, E Frisan, O Beyne-Rauzy

  • 1Department of Hematology, Cochin Institute, Paris, France.

Leukemia
|July 11, 2008
PubMed

Insights

Myelodysplastic syndromes (MDS) anemia stems from bone marrow cell death. Endoplasmic reticulum (ER) targeted Bcl-2 protein inhibits this apoptosis by preventing BAP31 cleavage, offering a potential therapeutic target.

Area of Science:

  • Hematology
  • Cell Biology
  • Molecular Medicine

Background:

  • Anemia in low-grade myelodysplastic syndromes (MDS) is primarily caused by spontaneous apoptosis of bone marrow erythroid precursors.
  • Fas-dependent activation of caspase-8 has been identified as a key mechanism in the death of these precursors.

Purpose of the Study:

  • To investigate the specific pathway linking caspase-8 activation to apoptosis in MDS erythroid precursors.
  • To explore the role of the endoplasmic reticulum (ER) and its associated proteins in this apoptotic process.

Main Methods:

  • Transduction of MDS bone marrow CD34(+) cells with lentivirus encoding wild-type (WT) or ER-targeted Bcl-2.
  • Induction of erythroid differentiation and assessment of apoptosis.
  • Analysis of mitochondrial membrane potential, cytochrome c release, ER Ca(2+) stores, and BAP31 cleavage.

Main Results:

  • Both WT-Bcl-2 and ER-targeted Bcl-2 effectively prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors.
  • ER-targeted Bcl-2 inhibited mitochondrial depolarization and cytochrome c release, implicating the ER upstream of mitochondria.
  • Caspase-8 cleaved ER-associated BAP31 in apoptotic MDS erythroid precursors, and ER-targeted Bcl-2 inhibited this cleavage.
  • Erythropoietin demonstrated a protective effect against Fas-induced BAP31 cleavage and apoptosis.

Conclusions:

  • Apoptosis in MDS erythroid precursors involves the endoplasmic reticulum, acting downstream of Fas and upstream of mitochondria.
  • Cleavage of the ER-associated protein BAP31 by caspase-8 is a critical step in this apoptotic pathway.
  • Targeting the ER-BAP31 pathway presents a potential therapeutic strategy for MDS-related anemia.

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