Apoptosis, bcl-2 Expression and p53 Accumulation in Myelodysplastic Syndrome, Myelodysplastic-Syndrome-Derived Acute Myelogenous Leukemia and de novo Acute Myelogenous Leukemia

Abstract

Apoptosis and its dysregulation have been implicated in dysplastic and ineffective hematopoiesis and the neoplastic transformation of bone marrow in myelodysplastic syndrome (MDS). To explore the role of apoptosis in hematological disorders, we examined the frequency of apoptotic cells by the in situ end labeling method in bone marrow specimens from 37 patients with MDS [refractory anemia (RA) 10 cases, RA with excess of blasts (RAEB) 27 cases including 12 cases with leukemic transformation], 12 patients with MDS-derived acute myelogenous leukemia (AML) and 13 patients with de novo AML. In addition, we investigated the relationship of apoptosis to the immunohistochemical expression of bcl-2 and p53 in these cases, and the association of apoptosis, bcl-2, and p53 with the leukemic evolution of MDS by examining sequential bone marrow samples of the same patient from the time of initial diagnosis to the time of overt leukemia. The percentage frequency of apoptotic cells was significantly greater in MDS (RA: 9.46 ± 2.99%, m ± SD; RAEB: 5.60 ± 3.09) as compared with those in MDS-derived AML (0.62 ± 0.37), de novo AML (0.28 ± 0.11) and controls (1.00 ± 0.59). On the other hand, the cases of RAEB with leukemic transformation exhibited a lower frequency of apoptotic cells and a higher frequency of bcl-2- and p53-positive cells than those without transformation. When the RAEB cases transformed to AML, the frequency of apoptotic cells was significantly reduced (2.96 ± 1.54 → 0.62 ± 0.37), while the frequencies of bcl-2-positive cells and p53-positive cells were greater (10.88 ± 3.66 → 30.54 ± 7.14, and 20.21 ± 6.21 → 32.34 ± 14.71, respectively). In contrast to MDS-derived AML, over a half of de novo AML cases showed few p53-positive cells. These findings corroborate the earlier notion that apoptosis may play a substantial role in dysplastic and ineffective hematopoiesis in MDS. It is also suggested that the suppression of apoptosis associated with enhanced bcl-2 expression and p53 accumulation increases the probability of developing leukemia in MDS, and that oncogenetic development might be different between MDS-derived AML and de novo AML.