Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Boudard, Delphine; Sordet, Olivier; Vasselon, C; Revol, Valérie; Bertheas, M. F.; Freyssenet, Damien; Viallet, Annie; Piselli, S; Guyotat, Denis; Campos, Lydia

doi:10.1038/sj.leu.2401959

Cited by 46 publications

(35 citation statements)

References 25 publications

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“…Recently a beneficial effect of caspase 3 inhibition on clonogenic Leukemia potential was strongly supported by a French study, showing significantly higher caspase 3 activity in RA/RARS vs other MDS subtypes, and that the inhibitor DEVD-cho was significantly enhanced in particular erythroid colony growth in these subtypes. 39 Similar to what we observed, there was no effect of caspase inhibition on normal bone marrow. Thus, there is now multiple evidence that increased caspase activation plays an important role in ineffective erythropoiesis.…”

Section: Discussionsupporting

confidence: 86%

“…In our previous study, we showed that a short caspase inhibition of CD34 + cells before plating could improve erythroid clonogenic growth 27 and the French study adding caspase inhibition during the whole culture period showed even stronger positive effects. 39 We also showed that erythroid cells at the GPA+ level was not affected by caspase inhibition, and that caspase activity was lower in this compartment, suggesting that the important steps in erythroid apoptosis in RARS occur at maturation levels before GPA+ cells. The caspase assay is a cell consuming method and we did not have the opportunity to apply it on purified CD34 + cells from more than one RARS and one control (data not shown).…”

Section: Figurementioning

confidence: 53%

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Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts

Schmidt-Mende

Tehranchi²,

Forsblom³

et al. 2001

Leukemia

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Treatment with granulocyte colony-stimulating factor (G-CSF) plus erythropoietin may synergistically improve hemoglobin levels and reduce bone marrow apoptosis in patients with refractory anemia with ringed sideroblasts (RARS). Fasinduced caspase activity is increased in RARS bone marrow cells. We showed that G-CSF significantly reduced Fasmediated caspase-8 and caspase-3-like activity and the degree of nuclear apoptotic changes in bone marrow from nine RARS patients. A decrease in mitochondrial membrane potential and an increase in intracellular reactive oxygen species occurred in Fas-treated cells, but became significant only 24 h after changes in caspase activity and decrease in proliferation. G-CSF also reduced the magnitude of these late apoptotic changes. In CD34-selected normal cells, G-CSF induced myeloid colony growth, and an overall small decrease in the number of erythroid colonies. By contrast, G-CSF induced a 33-263% increase of erythroid colony formation in CD34 + cells from four of five RARS patients with severely reduced erythroid growth, while the normal or slightly reduced erythroid growth of three other patients was not influenced by G-CSF. This study suggests that G-CSF may reduce the pathologically increased caspase activity and concomitant apoptotic changes, and promote erythroid growth and differentiation of stem cells from RARS patients. Our data support the clinical benefit of G-CSF in this subgroup of myelodysplastic syndromes. Leukemia (2001) 15, 742-751.

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Section: Discussionsupporting

confidence: 86%

Section: Figurementioning

confidence: 53%

Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts

Schmidt-Mende

Tehranchi²,

Forsblom³

et al. 2001

Leukemia

View full text Add to dashboard Cite

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“…These studies could also provide new insights in the mechanisms of caspase activation and abnormal differentiation associated with early phases of myelodysplastic syndromes. 47,48 …”

Section: Discussionmentioning

confidence: 99%

Specific involvement of caspases in the differentiation of monocytes into macrophages

Sordet

Rébé

Plenchette

et al. 2002

Blood

289

266

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Caspases are cysteine proteases involved in apoptosis and cytokine maturation. In erythroblasts, keratinocytes, and lens epithelial cells undergoing differentiation, enucleation has been regarded as a caspase-mediated incomplete apoptotic process. Here, we show that several caspases are activated in human peripheral blood monocytes whose differentiation into macrophages is induced by macrophage colony-stimulating factor (M-CSF). This activation is not associated with cell death and cannot be detected in monocytes undergoing dendritic cell differentiation in the presence of interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The mechanisms and consequences of caspase activation were further studied in U937 human monocytic cells undergoing phorbol ester-induced differentiation into macrophages. Differentiation-associated caspase activation involves the release of cytochrome c from the mitochondria and leads to the cleavage of the protein acinus while the poly(ADP-ribose)polymerase remains uncleaved. Inhibition of caspases by either exposure to the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-DL -Asp-fluoromethylketone (z-VAD-fmk) or expression of the p35 baculovirus inhibitory protein or overexpression of Bcl-2 inhibits the differentiation process. In addition, z-VAD-fmk amplifies the differentiation-associated production of radical oxygen species in both phorbol ester-differentiated U937 cells and M-CSF-treated monocytes, shifting the differentiation process to nonapoptotic cell death. Altogether, these results indicate that caspase activation specifically contributes to the differentiation of monocytes into macrophages, in the absence of cell death. IntroductionA family of cysteine proteases known as caspases plays a central role in many forms of apoptosis. 1 These enzymes are synthesized as inactive zymogens that must be cleaved after conserved aspartate residues to be activated. Two main pathways were shown to trigger caspase activation in cells undergoing apoptosis. 2 Schematically, the intrinsic pathway involves the disruption of the outer mitochondrial membrane barrier function, thus permitting the release of proapoptotic molecules from the mitochondria to the cytosol. One of these molecules is cytochrome c, which, once in the cytosol, oligomerizes the adaptor molecule Apaf-1 to recruit and activate the initiator caspase-9. In turn, caspase-9 cleaves and activates downstream effector enzymes such as caspase-3. The extrinsic pathway to cell death involves plasma membrane death receptors. In response to their engagement, these receptors trimerize and recruit the adaptor molecule Fas-associated death domain protein (FADD), which, in turn, interacts with and activates an initiator enzyme, usually caspase-8. This enzyme, either directly or through the previously described mitochondrial pathway, activates downstream effector enzymes including caspase-3. 3 In both pathways, effector caspases trigger the limited proteolytic cleavage of intracellular structural and regulatory p...

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“…Both of these techniques can be used to examine the induction of apoptosis. [46][47][48][49][50] An example of these techniques is presented in Figure 6.…”

Section: Pi3k Is Required For Mek1-mediated Growthmentioning

confidence: 99%

Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia

et al. 2003

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Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Cited by 46 publications

References 25 publications

Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts

Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts

Specific involvement of caspases in the differentiation of monocytes into macrophages

Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia

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