Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia.

Autor:	Del Papa B; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Baldoni S; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy.; Department of Life, Health and Environmental Sciences, Hematology Section, University of L'Aquila, L'Aquila, Italy., Dorillo E; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., De Falco F; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Rompietti C; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Cecchini D; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Cantelmi MG; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Sorcini D; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Nogarotto M; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Adamo FM; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Mezzasoma F; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Silva Barcelos EC; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy.; Department of Biological Sciences, Postgraduate Program in Biotechnology (UFES), Federal University of Espirito Santo, Vitória-ES, Brazil., Albi E; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Iacucci Ostini R; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Di Tommaso A; Department of Life, Health and Environmental Sciences, Hematology Section, University of L'Aquila, L'Aquila, Italy., Marra A; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Montanaro G; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy.; Department of Hematology, Transfusion Medicine and Biotechnologies, Ospedale Civile, Pescara, Italy., Martelli MP; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Falzetti F; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy., Di Ianni M; Department of Hematology, Transfusion Medicine and Biotechnologies, Ospedale Civile, Pescara, Italy.; Department of Medicine and Aging Sciences, University of Chieti Pescara, Chieti, Italy., Rosati E; Department of Experimental Medicine, Biosciences and Medical Embriology Section, University of Perugia, Perugia, Italy., Sportoletti P; Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy. paolo.sportoletti@unipg.it.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Dec 15; Vol. 25 (24), pp. 7540-7553. Date of Electronic Publication: 2019 Oct 02.
DOI:	10.1158/1078-0432.CCR-19-1009
Abstrakt:	Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many off-target effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response. Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the cross-talk between BTK and NOTCH1. Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphorylation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells. Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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