A PARADIGM SHIFT IN MYELODYSPLASTIC SYNDROMES

A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hemato poiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propose that this picture is further complicated by a variety of cytokines, tumor necrosis factor alpha (T NF-alpha), transforming growth factor beta (TGF-beta) and interleukin 1 beta (IL-1 beta) which exert a dual effect on the diseased cells. Th e immature CD34(+) cells are stimulated to proliferate, while their la ter differentiated daughters are induced to undergo apoptosis accounti ng for the clinical syndrome of pancytopenia despite hypercellular BMs . Studies directed at measuring the rates of proliferation and apoptos is as well as the levels of TNF-alpha, TGF-beta and IL-1 beta confirm this hypothesis and are presented in greater detail. A novel approach towards MDS therapy emerges as a result of this paradigm shift based u pon the premise that anti-cytokine therapy would prevent excessive int ramedullary apoptosis and result in improved cytopenias as well as cau se a slowing down of the diseased precursor cell proliferation resulti ng in resumption of polyclonal hematopoiesis. Because a number of cyto kines function through common lipid second messengers, interruption of this pathway should theoretically cause disruption in the signalling of a cascade of cytokines.