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Title: Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
Author: López-Guerra, Mónica
Xargay i Torrent, Sílvia
Fuentes, Patricia
Roldán, Jocabed
González Farré, Blanca
Rosich, Laia
Silkenstedt, Elisabeth
García León, María J.
Lee-Vergés, Eriong
Giménez Carabaza, Neus
Giró, Ariadna
Aymerich Gregorio, Marta
Villamor i Casas, Neus
Delgado, Julio
López Guillermo, Armando
Puente, Xose S.
Campo Güerri, Elias
Toribio, María L.
Colomer Pujol, Dolors
Keywords: Leucèmia limfocítica crònica
Chronic lymphocytic leukemia
Issue Date: 15-Oct-2019
Publisher: Macmillan Publishers
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.
Note: Reproducció del document publicat a:
It is part of: Oncogene, 2019, vol. 39, p. 1185-1197
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ISSN: 0950-9232
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Fonaments Clínics)

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