title: Ligation of cell surface CD38 protein with agonistic monoclonal antibody induces a cell growth signal in myeloid leukemia cells.
abstract: CD38 is expressed during early stages of differentiation in normal and leukemic myeloid cells. Recently, CD38 has been shown to participate in intracellular signal transduction pathways following its ligation with CD38-specific mAbs. In this study we report that ligation of CD38 by one such agonistic mAb (IB4) induced proliferation of cultured leukemic cells in vitro. In HL-60, KG-1A, NB4, and OCI-AML-3 myeloid leukemia cell lines, IB4 mAb induced an increase in the proliferating cell fraction as determined by cell number, clonogenic assay, and flow cytometric analysis. The presence of Ab caused a dose-dependent increase in the number of CFU and an increase in cell divisions. HL-60-Dox cells (a HL-60-doxorubicin-resistant cell line), which have no detectable CD38 expression, failed to respond to IB4 mAb. The effect of CD38 ligation on cell growth was also evaluated in freshly isolated leukemic cells from patients with acute myelogenous leukemia (AML). A significant increase in the proliferating cell fraction (S+G2M) was observed in 50% of the patients incubated with IB4 mAb. In five of the six AML patients, anti-CD38 mAb stimulated the proliferation of AML colony-forming cells. These results suggest that ligation of CD38 can induce the proliferation of leukemic cells and may play a role in the propagation of leukemic cell clones in certain cohorts of AML patients.
authors.affiliation: Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Konopleva
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
authors.forename: S
authors.initials: S
authors.lastname: Zhao
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.forename: K
authors.initials: K
authors.lastname: Mehta
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000276:immunology / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1