Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodysplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro

Bouscary, Didier; Chen, Yan Lian; Guesnu, Martine; Picard, Françoise; Viguier, Franck; Lacombe, Catherine; Dreyfus, François; Fontenay, Michaëla

doi:10.1016/s0301-472x(00)00179-x

Cited by 55 publications

(34 citation statements)

References 37 publications

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“…Again a higher efficiency of DEVD-cho was noted. Our findings are different to those recently reported by Bouscary et al 32 In this study as in ours, an enhanced caspase-3 activity was observed in early stage MDS, which was inhibited by Z-VAD-fmk. However, clonogenic assays in the presence of this inhibitor did not result in increased colony formation.…”

Section: Discussioncontrasting

confidence: 99%

Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Boudard¹,

Sordet

Vasselon

et al. 2000

Leukemia

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Myelodysplastic syndromes (MDS) are characterized by abnormal growth of committed progenitors in clonogenic assay, with reduced number of colonies and decreased colony/cluster ratio. It has been suggested that excessive apoptosis is the cause of marrow failure in MDS. We studied the expression of caspase-1 (interleukin-1␤-converting enzyme, ICE) and caspase-3 (CPP32/apopain) in marrow mononuclear cells, and the growth pattern of committed progenitors in a series of 83 MDS cases. The percentage of apoptotic cells as detected by TUNEL technique, and the percentage of caspase-3-positive cells were significantly higher in refractory anemia (RA) and RA with ringed sideroblasts (RAS) than in chronic myelomonocytic leukemia (CMML), refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T). Spontaneous growth of CFU-GM was associated with a higher percentage of blasts, and with a lower expression of caspase-3 and caspase-1. The yield of CFU-E, BFU-E, and CFU-GM (in the presence of growth factors) was decreased by comparison to normal marrow, but large individual differences were observed in all cytological categories. Inhibition of caspase-1 and caspase-3 activities by specific inhibitors resulted in a significant increase of the production of all types of colonies (up to 50-fold of control). In the presence of caspase-3 inhibitor, the number of BFU-E and CFU-E was in the range of normal values in most cases of RA and RAS. In addition, caspase-1 and -3 protease activities were detectable by fluorogenic assay in all cases studied. Western blot analysis confirmed the expression of caspase-3, including the cleaved (activated)-p17 form in most cases of RA/RAS analyzed. It is concluded that caspase-3 is implicated in the increased apoptosis observed in MDS and that inhibition of its activity can restore at least partially the growth of committed progenitors. Leukemia (2000) 14, 2045-2051.

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Section: Discussioncontrasting

confidence: 99%

Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Boudard¹,

Sordet

Vasselon

et al. 2000

Leukemia

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“…Other investigators have also reported that apoptosis was mainly seen in immature CD34+ progenitors, after separation of marrow cells into CD34+ and CD34− cell fractions [6,11,27]. The fact that apoptosis in the FAB low-risk group was higher than that in the FAB high-risk group, although not significantly different, is in accordance with a number of previous studies [1,6,10,11,25,28]. The increased apoptosis observed in "early" MDS is possibly a physiological mechanism whereby the hematopoietic system is able to eliminate potentially harmful Fig.…”

Section: Discussionsupporting

confidence: 89%

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

et al. 2009

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“…Ability of stem cells to respond to injury and disease may be compromised during aging, while proliferative potential of hematopoietic stem cells may be relatively maintained during aging under basal conditions. The high rate of apoptosis in BM of RA and RARS patients is in accordance with the data obtained by others [30] and confirms that the excessive apoptosis in patients with "early stage" myelodysplasia (RA, RARS) is a major characteristic of MDS. Excessive production of growth-inhibitory cytokines such as tumor necrosis factor (TNF-α) was demonstrated in BM plasma of patients with MDS [21][22][23][24]31].…”

Section: * * a B A Bsupporting

confidence: 91%

Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro‐apoptotic cytokines

Moldoveanu

Moicean

Vidulescu

et al. 2003

J Cellular Molecular Medi

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Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl‐2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl‐2 was performed using annexin V‐biotin conjugate antibody and anti‐human Bcl‐2 antibody respectively, followed by streptavidine‐peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl‐2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl‐2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl‐2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.

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Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodysplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro

Cited by 55 publications

References 37 publications

Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro‐apoptotic cytokines

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