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Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
Mónica López-Guerra1,2,3, Sílvia Xargay-Torrent1, Patricia Fuentes4
1Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Abstract:
Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.
Insights
DLL4 ligand stimulates Notch signaling and proliferation in NOTCH1-mutated chronic lymphocytic leukemia (CLL). An anti-Notch1 antibody, OMP-52M51, effectively blocks these effects, offering a targeted therapy for poor-prognosis CLL patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Notch signaling is a therapeutic target in chronic lymphocytic leukemia (CLL), especially in patients with NOTCH1 mutations.
- DLL4, a Notch ligand, is implicated in cancer cell growth and survival.
Purpose of the Study:
- To investigate the role of DLL4 in NOTCH1-mutated CLL.
- To evaluate the efficacy of the anti-Notch1 antibody OMP-52M51 in blocking DLL4-induced effects in CLL.
Main Methods:
- Assessed DLL4's effect on Notch signaling and proliferation in NOTCH1-mutated CLL cells.
- Examined DLL4 expression in lymph node histiocytes.
- Tested OMP-52M51's ability to inhibit DLL4-induced signaling and gene expression (MYC, CCND1, NPM1).
- Evaluated DLL4's impact on protumor genes (CXCR4, NRARP, VEGFA), cell migration, and angiogenesis.
Main Results:
- DLL4 potently stimulates Notch signaling and proliferation in NOTCH1-mutated CLL cells.
- DLL4 is expressed in lymph node histiocytes in both NOTCH1-mutated and -unmutated CLL.
- OMP-52M51 effectively blocks DLL4-induced Notch activation, MYC, CCND1, NPM1 expression, and proliferation.
- DLL4 stimulation increases protumor gene expression, cell migration, and angiogenesis, all antagonized by OMP-52M51.
Conclusions:
- DLL4 plays a significant role in NOTCH1-mutated CLL progression.
- Targeting Notch1 with OMP-52M51 is a promising therapeutic strategy for this poor-prognosis CLL subgroup.
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