Abstract
Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in B-ALL chemosensitivity. We observed significant Notch receptor and ligand expression in B-ALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of B-ALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-κB, and ERK expression. In NOG-mouse-based xenograft models of B-ALL, co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with B-ALL.Significance: Inhibition of Notch signaling enhances the chemosensitivity of B-ALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with B-ALL.
Highlights
B-cell acute lymphoblastic leukemia (B-ALL) is the most common leukemia in pediatric population; nowadays, more than 90% of all patients obtain disease complete remission following treatment, but the prognosis for relapsed/refractory patients or adult B-ALL patients is still poor [1]
The pathologic role of Notch signaling in T-acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL) is often linked to the mutational status of the pathway
None of the activating Notch point mutations observed in T-ALL and CLL was present in B-ALL samples
Summary
B-cell acute lymphoblastic leukemia (B-ALL) is the most common leukemia in pediatric population; nowadays, more than 90% of all patients obtain disease complete remission following treatment, but the prognosis for relapsed/refractory patients or adult B-ALL patients is still poor [1]. We previously observed high expression of Notch ligands and receptors in a subset of 12 patients with B-ALL, as well as in stromal cells from patients with B-ALL This evidence suggested a Notch paracrine signaling between B-ALL cells and their microenvironment, whose abrogation through Notch inhibitors, such as gamma-secretase inhibitors (GSI), resulted in B-ALL cells apoptosis [14]. We demonstrated that Notch pathway inhibition sensitizes B-ALL cells to drugs by increasing intracellular levels of ROS, promoting the reduction of B-ALL cell survival both in vitro and in vivo. These findings represent a preclinical rationale for combination treatments including Notch inhibitors and chemotherapy
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