SIMULTANEOUS ASSESSMENT OF CELL-KINETICS AND PROGRAMMED CELL-DEATH INBONE-MARROW BIOPSIES OF MYELODYSPLASTICS REVEALS EXTENSIVE APOPTOSIS AS THE PROBABLE BASIS FOR INEFFECTIVE HEMATOPOIESIS

Despite hypercellular bone marrows (BM), peripheral cytopenias are the rule in patients with myelodysplastic syndromes (MDS), This study exa mined the roles played by cell birth and cell death rates in generatin g this paradox, Cell kinetics from BM biopsies of 35 MDS patients were measured using intravenous infusions of either iododeoxyuridine or br omodeoxyuridine, or both, Degree of apoptosis or programmed cell death (PCD) was estimated using in situ end-labeling of DNA directly from B M biopsies, which were simultaneously double-labeled for proliferation /PCD. MDS were found to be highly proliferative disorders with large n umbers of myeloid, erythroid, and megakaryocytic cells synthesizing DN A, Median cycling time (Tc) of myeloblasts was more rapid than that of patients with acute myeloid leukemia (44.1 hr vs. 56.0 hr). Interesti ngly, most marrow cells of all three lineages in 32 of 34 evaluable ca ses were undergoing PCD, In 19 of 32 patients, greater than 75% cells were apoptotic, Surprisingly, large numbers of S-phase cells were foun d to be simultaneously undergoing PCD, as were stromal cells of the BM microenvironment. We conclude that the extensive apoptosis in hematop oietic cells effectively cancels the high birth rate resulting in inef fective hematopoiesis and accounting for deficient bone marrow functio n. (C) 1995 Wiley-Liss, Inc.