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2019-10-15

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cc by (c) Macmillan Publishers, 2019
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/172249

Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

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Recurs relacionat

https://doi.org/10.1038/s41388-019-1053-6

Resum

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.

Matèries

Leucèmia limfocítica crònica, Angiogènesi

Matèries (anglès)

Chronic lymphocytic leukemia, Neovascularization

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Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

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 (delgado gonzález), LÓPEZ GUILLERMO, Armando, PUENTE, Xose s., CAMPO GÜERRI, Elias, TORIBIO, María l., COLOMER PUJOL, Dolors. Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. _Oncogene_. 2019. Vol. 39, núm. 1185-1197. [consulta: 25 de febrer de 2026]. ISSN: 0950-9232. [Disponible a: https://hdl.handle.net/2445/172249]

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