CD38 ligation inhibits normal and leukemic myelopoiesis

CD38 is a transmembrane molecule whose expression varies during hematopoietic cell differentiation. We used stroma-supported cultures of human myeloid cells to assess the effects of CD38 ligation on myeloid differentiation. In 8 experiments with CD34⁺ cells purified from normal bone marrow or cord blood, flow cytometry used with antibodies to CD34 and myeloperoxidase (MPO) identified 4 cell populations after 7 days of culture. Addition of anti-CD38 (T16) to the cultures induced a profound reduction of the most mature (CD34-MPO⁺⁺) cell population, which includes promyelocytes, myelocytes and metamyelocytes; mean (± SD) cell recovery was 12,8% ± 9.8% of that in parallel cultures with an isotype-matched control antibody. The suppressive effect of CD38 ligation on phenotypically more immature normal cells was inconsistent but generally less pronounced. Recovery of CD34⁺⁺MPO^- cells was 63.3% ± 24.4%, recovery of CD34[(+/-)] MPO- cells was 95.3% ± 35.1%, and recovery of CD34-MPO⁺ cells was 42.0% ± 18.7% of that in control cultures. However, anti-CD38 suppressed recovery of cells obtained from 6 patients with CD38⁺ acute myeloid leukemia; after 7-day cultures, cell recovery was 25.2% ± 21.7% of that in control cultures. Cell recovery was also reduced by F(ab')₂ or Fab fragments of anti-CD38. CD38 ligation dramatically suppressed recovery of murine 32D myeloid cells transfected with human CD38 and cocultured with stroma (3.8% ± 7.3%; n = 7). CD38 ligation of CD38⁺ 32D cells also induced cell aggregation, tyrosine kinase activity, and Ca⁺⁺ influx. We conclude that CD38 mediates signals that culminate in suppression of myeloid cell growth and survival.