γ-Secretase inhibitors suppress the growth of leukemia and lymphoma cells

Abstract

γ-Secretase inhibitors (GSI) suppress the growth of acute T-lymphoblastic leukemia (T-ALL) cells with NOTCH1 mutations. Recently, clinical trials of GSI for refractory T-ALL have commenced. In the present study, we examined the effects of three types of GSI; GSI-I, GSI-IX, and GSI-XII on the growth of four B-cell malignant lymphoma (B-ML) and four acute myeloid leukemia (AML) cell lines as well as four T-ALL cell lines. We found that GSI also suppressed the in vitro growth of some B-ML and AML cell lines in a dose-dependent manner. Growth suppression occurred through induction of apoptosis. Expression of the HES1 gene, one of the targets of Notch signaling, was high in T-ALL cells with NOTCH1 mutations, but was low in GSI-sensitive B-ML and AML cells. GSI treatment decreased HES1 mRNA expression in T-ALL cells, while GSI increased HES1 mRNA in two GSI-sensitive B-ML and AML cell lines. In immunoblot analysis, the band for the intracellular fragment of Notch1, an active form of Notch1, was dense in T-ALL cells but was faint in GSI-sensitive B-ML and AML cells; attenuation of the band by GSI was not evident. These findings suggest that GSI may act on Notch 2, 3 or 4 protein, or some pathways other than Notch signaling in GSI-sensitive B-ML and AML cells. Namely, growth suppression by GSI may involve cell growth-related proteins, which are γ-secretase substrates. Taken together, we have shown that GSI may be useful for the treatment of hematological malignancies other than T-ALL. The mechanism behind the effects remains to be clarified. Our investigations lead to a novel molecular target therapy for chemotherapy-resistant leukemia and lymphomas.