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Notch‐Regulation upon Dll4‐Stimulation of TGFb‐Induced Apoptosis and Gene Expression in Human B‐Cell Non‐Hodgkin Lymphomas
Author(s) -
Hajdu M.,
Kopper L.,
Sebestyén A.
Publication year - 2009
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2009.02346.x
Subject(s) - apoptosis , notch signaling pathway , cancer research , microbiology and biotechnology , programmed cell death , biology , signal transduction , cell growth , genetics
Notch‐signalling has been implicated as a pathogenetic factor and a therapeutical target in T‐cell leukaemias and in some lymphomas of B‐cell origin. Our aim was to investigate the role of Notch‐signalling in apoptosis regulation in human non‐Hodgkin B‐cell lymphoma (B‐NHL) cell lines and in primary chronic lymhocytic leukaemia (CLL) cells using Delta‐like 4 (Dll4) ligand mediated Notch activation and gamma‐secretase inhibitor (GSI) mediated Notch inhibition in vitro . The potential cross‐talk of Notch with the transforming growth factor‐beta (TGFb) pathway in apoptosis induction was also explored, and the effect of GSI on drug‐induced apoptosis was assessed. Modulation of Notch‐signalling by itself did not change the rate of apoptosis in B‐NHL cell lines and in CLL cells. TGFb‐induced apoptosis was decreased – but not completely abolished – by GSI in TGFb‐sensitive cell lines, but resistance to the apoptotic effects of TGFb were not reversed by Notch activation or inhibition. Drug‐induced apoptosis was not modified by GSI. We identified Hairy/Enhancer of Split (HES)‐1 as a TGFb target gene in selected – TGFb‐sensitive – B‐NHL cell lines. TGFb‐induced HES‐1 was only partially Notch‐dependent in later phases. Apoptosis regulation by TGFb and GSI was not dependent on the transcriptional regulation of c‐myc. In conclusion, our data does not support a unifying role of Notch in regulating apoptosis in B‐NHL, but warns that gamma‐secretase inhibitors may actually counteract apoptosis in some cases.