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• W4254132561 abstract "We thank Dr. Raza and her coworkers for commenting on our article concerning the role of caspases in MDS [1Bouscary D. Chen Y.L. Guesnu M. et al.Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodyplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000; 28: 784Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. As underlined by these authors, increased apoptosis in MDS results from activation of a family of cytosolic proteases termed caspases. Caspase-1 and caspase-3/CPP32 are processed to generate active enzymes in MDS [1Bouscary D. Chen Y.L. Guesnu M. et al.Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodyplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000; 28: 784Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Ali A. Mundle S.D. Ragasa D. et al.Sequential activation of caspase-1 and caspase-3-like proteases during apoptosis in myelodysplastic syndromes.J Hematother Stem Cell Res. 1999; 8: 343Crossref PubMed Scopus (27) Google Scholar, 3Mundle S.D. Venugopal P. Cartlidge J.D. et al.Indication of an involvement of interleukin-1β converting enzyme-like protease in intramedullary apoptic cell death in the bone marrow of patients with myelodysplastic syndromes.Blood. 1996; 88: 2640PubMed Google Scholar]. The implication of caspases in the process of apoptosis in MDS is not surprising, since caspase-independent apoptotic signal transduction pathways are rare. Further determination of the cascade of caspases activated in MDS is now needed. A cytokine-mediated process has been proposed to explain apoptosis in these disorders, possibly implicating tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The Fas/Fas-ligand system may be involved as well, leading to the cleavage of initiator caspases such as caspase-8 and 10. The description of this pathway of apoptosis is of great importance in order to develop new therapeutic tools. It is also important to determine whether the apoptotic phenotype can be reversed, which might ameliorate the ineffective hematopoiesis observed in MDS. The best demonstration that it is possible arises from studies demonstrating that patients responding to erythropoietin and granulocyte colony-stimulating factor have reduced apoptosis of hematopoietic cells [4Rajapaksa R. Ginzton N. Rott L.S. Greenberg P.L. Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells.Blood. 1996; 88: 4275PubMed Google Scholar, 5Hellstrom-Lindberg E. Kanter-Lewensohn L. Ost A. Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-CSF and erythropoietin.Leuk Res. 1997; 21: 415Abstract Full Text PDF PubMed Scopus (114) Google Scholar]. The use of peptide inhibitors of caspase activation have also shown that these proteins are really implicated in apoptosis. In our study, the percentage of apoptotic cells was diminished in 44% of patients with “early-stage” MDS and increased apoptosis [1Bouscary D. Chen Y.L. Guesnu M. et al.Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodyplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000; 28: 784Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. The discrepancy between our results and those published by Raza et al. [2Ali A. Mundle S.D. Ragasa D. et al.Sequential activation of caspase-1 and caspase-3-like proteases during apoptosis in myelodysplastic syndromes.J Hematother Stem Cell Res. 1999; 8: 343Crossref PubMed Scopus (27) Google Scholar] who found a decrease of apoptotic cells in all eight patients studied may be related to the different times of incubation (4 hours vs 12 hours in our report), to the different concentrations of Z-VAD-FMK utilized (10 μM vs 100-500 μM), to biological differences between the patients studied, and finally to the culture conditions utilized (medium culture without SVF and added cytokines). The concentrations of Z-VAD-FMK used to inhibit apoptosis in our MDS patients (100–500 μM) were determined according to those necessary to reverse etoposide-induced apoptosis of normal bone marrow mononuclear cells. At 50 μM of Z-Vad, the percentage of annexin-V+ cells was not significantly reduced, but a 50% inhibition was observed at 100 μM. We were not, however, able to enhance hematopoiesis in vitro using these peptide inhibitors. In the conditions we described, caspase inhibition is insufficient to enhance the in vitro growth of mature erythroid and myeloid progenitors. The abstract by Campos et al. [6Campos L. Sabido O. Viallet A. et al.Implication of ICE and CPP32 in the in vitro defects of committed progenitors from myelodysplastic syndromes.Blood. 1997; 90: 521aGoogle Scholar] referenced by Raza reported increased colony formation in MDS patients using the YVAD and DEVD caspases-inhibitors known to have a restricted specificity for caspases compared to Z-VAD-FMK. The reasons for the discrepancy between the two studies [1Bouscary D. Chen Y.L. Guesnu M. et al.Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodyplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000; 28: 784Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 6Campos L. Sabido O. Viallet A. et al.Implication of ICE and CPP32 in the in vitro defects of committed progenitors from myelodysplastic syndromes.Blood. 1997; 90: 521aGoogle Scholar] are unknown, because we also used DEVD (unpublished results) with no more success than with Z-VAD. However, our results do not eliminate the possibility that peptide inhibitors used in a different fashion, by direct exposure of CD34+ hematopoietic stem cells (where apoptosis seems to originate in MDS), and/or by using midterm liquid cultures instead of clonogenic progenitor assays, may improve hematopoiesis in some subtypes of MDS by direct inhibition of caspases. Alternatively, and as described in many systems of programmed cell death, activation of effector caspases in MDS progenitor cells may irreversibly commit these cells to die. The second point emphasized by Raza et al. is of great technical importance. They indicate that the percentages of apoptotic cells must be interpreted according to the technique used to study apoptosis and to the cellular population analyzed. Her recently published data convincingly indicate that it is necessary to study apoptosis both in the high-density (HD) and low-density (LD) fractions of Ficoll-Hypaque separated bone marrow cells, demonstrating that apoptotic cells are mainly represented in the HD fraction that must be carefully recovered [7Shetty V. Hussaini S. Broady-Robinson L. et al.Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndromes can be massive Apoptotic cells recovered from high density fraction of bone marrow cells.Blood. 2000; 96: 1388PubMed Google Scholar]. We agree with these conclusions. These observations explain in part the different rates of apoptosis we observe when the same patients are studied for apoptosis by TUNEL on bone marrow smears and by using the flow cytometry annexin-V binding assay performed on the LD fraction (44% vs 36%). However, this argument does not explain the discrepancy between our results using the TUNEL assay on bone marrow smears and those reported by Raza et al. [8Raza A. Gezer S. Mundle S. et al.Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995; 86: 268Crossref PubMed Google Scholar] using the ISEL technique on bone marrow biopsies. Using TUNEL on bone marrow smears representative of all hematopoietic cells, we reproductively find that apoptosis is increased in MDS patients with “early-stage” disease (ESD) and decreased or identical to normal controls (NC) in “late-stage” disease (LSD) (44.2% in ESD, 11% in LSD, and 12% in NC) [1Bouscary D. Chen Y.L. Guesnu M. et al.Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodyplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000; 28: 784Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 9Fontenay-Roupie M. Bouscary D. Guesnu M. et al.Ineffective erythropoiesis in myelodysplastic syndromes Correlation with Fas expression but not with lack of erythropoietin signal transduction.Br J Haematol. 1999; 106: 464Crossref PubMed Scopus (65) Google Scholar, 10Bouscary D. De Vos J. Guesnu M. et al.Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes.Leukemia. 1997; 11: 839Crossref PubMed Scopus (157) Google Scholar]. ISEL carried out in bone marrow biopsy sections gives higher apoptosis rates at all stages of MDS [8Raza A. Gezer S. Mundle S. et al.Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995; 86: 268Crossref PubMed Google Scholar]. Our results in ESD are in agreement with the data of Raza et al. [8Raza A. Gezer S. Mundle S. et al.Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995; 86: 268Crossref PubMed Google Scholar] because stromal cells that they described as apoptotic are not well represented in our bone marrow smears and also because the local concentrations of inhibitory cytokines may be effectively more concentrated in the biopsy compartment. However, for patients with blastic disease, we do not understand the difference, in part because patients with RAEB seem to not have increased levels of TNF-α1 [11Molnar L. Berki T. Hussain A. Nemeth P. Losonczy H. Detection of TNF-α expression in the bone marrow and determination of TNF-α production of peripheral blood mononuclear cells in myelodysplastic syndromes.Pathol Oncol Res. 2000; 1: 18Crossref Scopus (32) Google Scholar]. Many groups agree that blasts cells (mostly CD34+) are not involved in the process of apoptosis as the disease progress. This point is finally the most important. It is fundamental to understand the biological mechanisms leading to apoptosis in ESD, whereas in LSD, it is necessary to restore efficient pro-apoptotic pathways in nonapoptotic blasts cells. Finally, the main challenge in MDS is actually to demonstrate if the susceptibility of the hematopoietic system to apoptosis is extrinsic or intrinsic to the hematopoietic stem cell itself. Resolution of this question will enhance our knowledge of the origin of myelodysplasia." @default.
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