NOVEL INSIGHTS INTO THE BIOLOGY OF MYELODYSPLASTIC SYNDROMES - EXCESSIVE APOPTOSIS AND THE ROLE OF CYTOKINES

The paradox of myelodysplastic syndromes (MDS) which present with panc ytopenias despite cellular bone marrows (BM) was investigated by condu cting detailed studies of proliferation and apoptosis in 89 MDS patien ts. Our results demonstrated a rapid rate of both proliferation as wel l as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleuk in-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alp ha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progeni tors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented, The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage l eading to monoclonal hemopoiesis, which in turn makes these cells susc eptible towards acquiring additional mutations and appearance of cytog enetically marked (or unmarked) clones. Cytokines such as TNF-alpha wh ose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.