Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 535-542
CD38 ligation inhibits normal and leukemic myelopoiesis
Elisabetta Todisco,
Toshio Suzuki,
Kleebsabai Srivannaboon,
Elaine Coustan-Smith,
Susana C. Raimondi,
Frederick G. Behm,
Akira Kitanaka, and
Dario Campana
From the Departments of Hematology-Oncology and Pathology, St. Jude
Children's Research Hospital, and University of Tennessee
College of Medicine, Memphis, TN; and First Department of Internal
Medicine, Kagawa Medical University, Japan.
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 CD34MPO+
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.
