2. Academic Validation
  3. Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy

Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy

  • J Exp Clin Cancer Res. 2019 Nov 1;38(1):446. doi: 10.1186/s13046-019-1458-7.
Elisabeth Silkenstedt 1 2 3,  Fabian Arenas 1 4,  Berta Colom-Sanmartí 1,  Sílvia Xargay-Torrent 1,  Morihiro Higashi 1,  Ariadna Giró 1 4,  Vanina Rodriguez 1,  Patricia Fuentes 5,  Walter E Aulitzky 6,  Heiko van der Kuip 3,  Sílvia Beà 4 7,  Maria L Toribio 5,  Elias Campo 4 7 8 9,  Mònica López-Guerra 1 4 8,  Dolors Colomer 10 11 12 13
Affiliations

Affiliations

  • 1 Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 2 Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany.
  • 3 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
  • 4 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 5 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
  • 6 Department of Hematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany.
  • 7 Lymphoid Neoplasm Program, IDIBAPS, Barcelona, Spain.
  • 8 Hematopathology Section, Hospital Clínic, Barcelona, Spain.
  • 9 University of Barcelona, Barcelona, Spain.
  • 10 Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. dcolomer@clinic.cat.
  • 11 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. dcolomer@clinic.cat.
  • 12 Hematopathology Section, Hospital Clínic, Barcelona, Spain. dcolomer@clinic.cat.
  • 13 University of Barcelona, Barcelona, Spain. dcolomer@clinic.cat.
PMID: 31676012 DOI: 10.1186/s13046-019-1458-7
Abstract

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.

Keywords

Angiogenesis; Delta-like ligand; Mantle cell lymphoma; Notch1; OMP-52 M51.

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