Notch ligands, Delta-1 and Delta-4 suppress the self-renewal capacity and long-term growth of two myeloblastic leukemia cell lines.
The self-renewal and differentiation of hematopoietic progenitors are regulated by the interaction between Notch receptors and Notch ligands. Since AML originates from dysregulated hematopoietic progenitors, some abnormalities in the Notch system may be involved in the abnormal proliferation of AML cells. However, the significance of the Notch system in AML is not known. We examined the functional roles of Notch activation on the in vitro growth of seven human AML cell lines using three kinds of recombinant Notch ligand proteins, Jagged-1, Delta-1 and Delta-4. The ligands significantly affected the growth of two cell lines. In TMD7 cells, Delta proteins promoted the short-term growth, however, suppressing the self-renewal capacity and long-term growth. In OCI/AML-6 cells, Delta proteins suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. We additionally found that Notch ligands needed to be immobilized on culture wells to affect the cells. These findings were in contrast to our hypothesis that Notch activation in AML cells leads to excessive self-renewal capacity and proliferation. If the Notch system in AML cells is precisely understood, the control of Notch activation will become a novel therapeutic approach for AML.
Tohda
Shuji
S
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. tohda.mlab@tmd.ac.jp
Murata-Ohsawa
Mai
M
Sakano
Seiji
S
Nara
Nobuo
N
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D011506:Proteins; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor