Related Experiment Video
Updated: Jan 31, 2026
In Ovo Xenografting of Patient-Derived Acute Lymphoblastic Leukemia (ALL) Cells (PDX-ALL)
Published on: August 1, 2025
Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia
Paul Takam Kamga1,2, Giada Dal Collo1, Martina Midolo1
1Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
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.
Insights
Inhibiting Notch signaling enhances chemotherapy effectiveness in B-cell acute lymphoblastic leukemia (B-ALL). This approach increases drug-induced cell death and reduces leukemic burden, offering a promising therapeutic strategy for B-ALL patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Notch signaling pathways are implicated in cell survival and drug resistance in various cancers.
- Notch3 and Notch4 receptors are known to support the survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells.
- Understanding Notch pathway's role in B-ALL chemosensitivity is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of the Notch pathway in B-ALL chemosensitivity using in vitro, in silico, and in vivo models.
- To evaluate the efficacy of Notch signaling inhibitors in combination with conventional chemotherapy agents against B-ALL.
- To elucidate the molecular mechanisms by which Notch inhibition affects B-ALL cell death.
Main Methods:
- Analysis of Notch receptor and ligand expression in primary B-ALL cells and cell lines.
- In vitro assessment of B-ALL cell survival treated with chemotherapeutic agents and Notch inhibitors (gamma-secretase inhibitors [GSI] and anti-Notch4).
- In vivo evaluation using NOG-mouse xenograft models treated with GSI-XII and cytarabine (Ara-C).
Main Results:
- Significant Notch receptor and ligand expression was observed in B-ALL cells, with high-risk patients overexpressing Notch3, Notch4, and Jagged2.
- Notch inhibitors (GSI and anti-Notch4) potentiated drug-induced B-ALL cell death by upregulating reactive oxygen species (ROS), modulating mTOR, NF-κB, and ERK pathways.
- Combination therapy with GSI-XII and Ara-C in a mouse xenograft model reduced leukemic burden and prolonged survival.
Conclusions:
- Notch signaling inhibition enhances the chemosensitivity of B-ALL cells.
- Targeting the Notch pathway presents a potential therapeutic strategy to improve outcomes for B-ALL patients.
- Combined inhibition of Notch signaling and chemotherapy offers a promising approach for B-ALL treatment.
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