Expression and activity of caspases 1 and 3 in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are characterized by abnormal growth of com mitted progenitors in clonogenic assay, with reduced number of colonies and decreased colony/cluster ratio. It has been suggested that excessive apopt osis is the cause of marrow failure in MDS. We studied the expression of ca spase-1 (interleukin-1 beta -converting enzyme, ICE) and caspase-3 (CPP32/a popain) in marrow mononuclear cells, and the growth pattern of committed pr ogenitors in a series of 83 NIDS cases. The percentage of apoptotic cells a s detected by TUNEL technique, and the percentage of caspase-3-positive cel ls were significantly higher in refractory anemia (RA) and RA with ringed s ideroblasts (RAS) than in chronic myelomonocytic leukemia (CMML), refractor y anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T). Spontaneous growth of CFU-GM was associated with a higher percentage of bla sts, and with a lower expression of caspase-3 and caspase-1. The yield of C FU-E, BFU-E, and CFU-GM tin the presence of growth factors) was decreased b y comparison to normal marrow, but large individual differences were observ ed in all cytological categories. Inhibition of caspase-1 and caspase-3 act ivities by specific inhibitors resulted in a significant increase of the pr oduction of all types of colonies (up to 50-fold of control). In the presen ce of caspase-3 inhibitor, the number of BFU-E and CFUE was in the range of normal values in most cases of RA and RAS. In addition, caspase-1 and -3 p rotease activities were detectable by fluorogenic assay in all cases studie d. Western blot analysis confirmed the expression of caspase-3, including t he cleaved (activated)-p17 form in most cases of RA/RAS analyzed. It is con cluded 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.