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Updated: Jan 4, 2026
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for
Elisabeth Silkenstedt1,2,3, Fabian Arenas1,4, Berta Colom-Sanmartí1
1Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Background:
NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target.
Methods:
Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo.
Results:
Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL.
Conclusion:
DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients.
Insights
NOTCH1 mutations in mantle cell lymphoma (MCL) drive disease progression. The anti-Notch1 antibody OMP-52M51 effectively targets these mutations, inhibiting tumor growth and angiogenesis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- NOTCH1 gene mutations occur in 5-10% of mantle cell lymphoma (MCL) cases.
- These mutations are linked to poorer patient survival outcomes.
- The study investigates the biological role and therapeutic potential of NOTCH1 mutations in MCL.
Purpose of the Study:
- To explore the biological impact of NOTCH1 mutations in MCL.
- To evaluate OMP-52M51 as a targeted therapy for NOTCH1-mutated MCL.
- To understand the role of DLL4 in MCL pathogenesis.
Main Methods:
- Assessed Notch1 signaling activation and OMP-52M51 inhibition using Western Blot and gene expression profiling.
- Evaluated OMP-52M51 effects on cell migration and angiogenesis via chemotaxis and HUVEC assays.
- Analyzed DLL4 expression in MCL lymph nodes and tested OMP-52M51 efficacy in a mouse model.
Main Results:
- DLL4 stimulation activated Notch1 signaling in NOTCH1-mutated MCL cells, unlike unmutated cells.
- OMP-52M51 blocked DLL4-induced Notch1 activation and suppressed target genes in mutated MCL cells.
- OMP-52M51 inhibited enhanced tumor cell migration and angiogenesis in NOTCH1-mutated MCL, with in vivo efficacy confirmed.
Conclusions:
- DLL4 stimulates Notch1 signaling in NOTCH1-mutated MCL, with DLL4 expressed by the tumor microenvironment.
- Targeted inhibition of Notch1-ligand interactions offers a potential therapeutic strategy for a subset of MCL patients.
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