[Functional analysis of notch in the pathophysiology of leukemia]

Notch signaling regulates the self-renewal and differentiation of hematopoietic stem cells. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic cells, the Notch system may be involved in the abnormal growth. We found that AML cells express not only Notch proteins but also Notch ligand proteins, which suggests the possibility of autonomous Notch activation. It is known that more than half of T-cell acute lymphoblastic leukemia (T-ALL) cases have activating mutations of the NOTCH1 gene. We report that one out of 20 AML samples and none out of 20 MDS samples showed NOTCH1 mutation. We established an AML cell line, TMD7, which proliferates in response to a Notch ligand, Dll1 protein. Notch activation by ligand stimulation suppressed the cytokine-induced differentiation and apoptosis of U937 cells. For OCI/AML-6 and THP1 cells, Notch ligands suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. For primary AML cells, the Notch ligands exhibited diverse effects on the short-term growth. The ligands reduced the self-renewal capacity and induced differentiation in some samples. For NOTCH1-mutated T ALL cells, gamma-secretase inhibitors(GSI), which block Notch activation, suppress the growth. We found that GSI suppressed the in vitro growth of some B-cell lymphoma and AML cell lines without NOTCH1 mutations through the induction of apoptosis. GSI may be useful as a novel molecular target therapy for various leukemias. For this purpose, we have to clarify the mechanism behind the effects. Laboratory tests regarding the expression and function of Notch will be important for individualized diagnosis and therapies.