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. (Blood. 2000;95:535-542)
Todisco
E
E
Departments of Hematology-Oncology and Pathology, St. Jude Children's Research Hospital, and University of Tennessee College of Medicine, Memphis, TN 38105-2794, USA.
Suzuki
T
T
Srivannaboon
K
K
Coustan-Smith
E
E
Raimondi
S C
SC
Behm
F G
FG
Kitanaka
A
A
Campana
D
D
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000502:physiology*; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D005312:Fetal Blood / Q000166:cytology; D006098:Granulocytes / Q000166:cytology* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D019891:Leukopoiesis / Q000276:immunology / Q000502:physiology*; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000235:genetics / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D011003:Ploidies; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D009195:Peroxidase; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium