Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment.

Apoptosis (programmed cell death) is an active cellular process which regulates cell population size by decreasing cell survival. In this review the underlying cellular and molecular mechanisms of apoptosis in hemopoietic and non-hemopoietic cells are described, with specific focus on these issues in the myelodysplastic syndrome (MDS), a myeloid clonal hemopathy. Apoptosis-regulating genes exist as families whose protein products are either anti-apoptotic or pro-apoptotic. Numerous stimuli can serve as initiators of the cell death pathway, including essentially all chemotherapeutic drugs, irradiation, certain inhibitory cytokines and deprivation of relevant growth factors. Morphological evidence of increased apoptosis in marrow hemopoietic cells has been demonstrated in patients with MDS. The reviewed data provide support for the hypothesis that early in MDS, increased apoptosis is associated with ineffective progenitor and maturing hemopoietic cell survival, and occurs concomitant with cytopenias/ineffective hemopoiesis; conversely, the progression of MDS toward AML occurs in concert with decreased apoptosis and an increased degree of neoplastic cell survival, leading to subsequent expansion of the abnormal precursor cells. These processes are associated with alterations in the balance between pro- and anti-apoptotic oncoprotein expression within the hemopoietic precursors, which may be modified by cytokine treatment. Investigations evaluating apoptotic events in MDS have improved our understanding of the biology of hemopoietic cell survival as related to pathogenetic features of this disease. By modifying levels of apoptosis, such studies provide a framework for future potentially beneficial therapeutic approaches to treat patients with MDS.