Diverse effects of the Notch ligands Jagged1 and Delta1 on the growth and differentiation of primary acute myeloblastic leukemia cells.
OBJECTIVE
Notch signaling plays a role in regulating the self-renewal and differentiation of hematopoietic progenitors. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic progenitors, the Notch system may be involved in the abnormal growth. We previously reported that AML cells express Notch proteins. In this study, we examined the effects of recombinant human Notch ligand proteins, Jagged1 and Delta1, on the growth and differentiation of primary AML cells.


METHODS
AML cells separated from blood from 12 patients were cultured in wells coated with Jagged1, Delta1, or control IgG. The short-term growth was evaluated using a colorimetric assay. The self-renewal capacity was evaluated by the clonogenic cells recovered, which were obtained via a colony assay involving cells cultured with the ligands or control IgG. Differentiation was evaluated by the morphology of the cultured cells and flow cytometric analysis.


RESULTS
The ligand stimulation caused three types of response in the short-term growth of the primary AML cells, namely, promotion, suppression, or no significant effect. The self-renewal capacity was suppressed or not significantly affected by the ligands, even in cells showing short-term growth promotion. The ligand stimulation altered blast cells into macrophage-like cells from their morphology and increased the expression of differentiation markers such as CD13 or CD14 in some samples.


CONCLUSIONS
The Notch ligands had diverse effects on the short-term growth of primary AML cells. The ligands did not promote the self-renewal capacity of any of the cells examined and instead tended to induce differentiation under the conditions used.
Tohda
Shuji
S
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan. tohda.mlab@tmd.ac.jp
Kogoshi
Hanae
H
Murakami
Naomi
N
Sakano
Seiji
S
Nara
Nobuo
N
D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology*; D008875:Middle Aged; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
D002135:Calcium-Binding 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; D051880:Receptors, Notch; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins; C064045:delta protein