Cyclic ADP-ribose (cADPR) is a universal second messenger that regulates many calcium-related cellular events by releasing calcium from intracellular stores. Since these events include enhanced cell proliferation and since the bone marrow harbors both ectoenzymes that generate cADPR from NAD(+) (CD38 and BST-1), we investigated the effects of extracellular cADPR on human hemopoietic progenitors (HP). Exposure of HP to 100 microM cADPR for 24 h induced a significant increase in colony output (P<0.01) and colony size (P<0.003). A horizontal expansion of HP, as demonstrated by a markedly increased replating efficiency in semisolid medium (up to 700 times compared to controls), was also observed, indicating that cADPR priming can affect cell growth for multiple generations over several weeks after exposure. Influx of extracellular cADPR into the cells was demonstrated, and a causal relationship between the functional effects and the increase of intracellular free calcium concentration induced by cADPR on HP was established through the use of specific antagonists. Similar effects on HP were produced by nanomolar concentrations of the nonhydrolyzable cADPR analog 3-deaza-cADPR. These data demonstrate that extracellular cADPR behaves as a cytokine enhancing the proliferation of human HP, a finding that may have biomedical applications for the ex vivo expansion of hemopoietic cells.

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We have studied the impact of cell dose on short-and long-term graft function and outcome in 905 patients undergoing an unmanipulated allogeneic bone marrow transplantation (BMT) from an HLAidentical sibling (n ‫؍‬ 735), a one-antigen mismatched related donor (n ‫؍‬ 35), or a matched unrelated donor (n ‫؍‬ 135). Median number of nucleated cells infused was 3.4 ؋ 10 8 /kg (25th percentile 2.4 ؋ 10 8 /kg, 75th percentile 5 ؋ 10 8 /kg). Patients were stratified according to cells infused in 3 groups: < 2.4 ؋ 10 8 /kg (n ‫؍‬ 247; low dose); >2.4 ؋ 10 8 /kg and < 5 ؋ 10 8 /kg (n ‫؍‬ 452; intermediate dose); and >5 ؋ 10 8 /kg (n ‫؍‬ 206; high dose). Patients receiving high cell dose had significantly higher platelet counts on days ؉20, ؉50, ؉100, ؉180, and ؉365 after BMT (P < .01) and higher white blood cell counts on days ؉50, ؉100, and ؉180 after BMT (P < .01) as compared with other patients. The actuarial 5-year transplantrelated mortality (TRM) was 41% versus 36% versus 28% (P ‫؍‬ .01); overall survival was 45% versus 51% versus 56% (P ‫؍‬ .0008); and disease-free survival was 41% versus 42% versus 48%, respectively, (P ‫؍‬ .04) in patients receiving low, intermediate, or high cell dose. The cell dose effect was more pronounced in patients older than 30 years of age, with advanced disease, with chronic myeloid leukemia, and with alternative donors. In multivariate Cox analysis on TRM, cell dose was a significant predictor (P ‫؍‬ .002; relative risk 0.6) together with donor type (P ‫؍‬ .0001), year of transplantation (P ‫؍‬ .0001), conditioning regimen (P ‫؍‬ .02), and recipient age (P ‫؍‬ .02). In conclusion, transplantation of high marrow cell dose is associated with reduced transplant mortality and improved survival and results in improved graft function both short and long term. (Blood. 2002;100:3930-3934)

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