Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells

Rosati, E.; Sabatini, R.; Rampino, G.; Tabilio, A.; Di Ianni, M.; Fettucciari, K.; Bartoli, A.; Coaccioli, S.; Screpanti, Isabella; Marconi, P.

doi:10.1182/blood-2008-02-139725

Notch signaling is involved in tumorigenesis, but its role in B-chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor kappa B (NF-kappa B) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein ( XIAP) expression. In contrast, Notch-signaling inhibition by the gamma-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-kappa B activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target. (Blood. 2009;113:856-865)

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Titolo:	Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells
Autori:	E. Rosati R. Sabatini G. Rampino A. Tabilio M. Di Ianni K. Fettucciari A. Bartoli S. Coaccioli SCREPANTI, Isabella P. Marconi mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2009
Rivista:	BLOOD
Handle:	http://hdl.handle.net/11573/14645
Appartiene alla tipologia:	01a Articolo in rivista

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