hes1-protein--human and Lymphoma--B-Cell

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Homeodomain Proteins; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Receptors, Notch; Signal Transduction; Transcription Factor HES-1

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.

Topics: Adaptor Proteins, Signal Transducing; Amyloid Precursor Protein Secretases; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Calcium-Binding Proteins; Cell Line, Tumor; Dipeptides; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Receptors, Notch; Repressor Proteins; Signal Transduction; Transcription Factor HES-1; Transforming Growth Factor beta

A novel lymphoma cell line, designated TMD8 was established from cells of a patient with diffuse large B-cell lymphoma. TMD8 cells expressed HES1 mRNA, suggesting constitutive activation of Notch signaling. TMD8 cells expressed normal-sized Notch1 protein, and showed no mutations in the NOTCH1 gene. Cell growth was suppressed by gamma-secretase inhibitors (GSI). It was reported that GSI suppressed growth of T-cell acute lymphoblastic leukemia (T-ALL) cell lines, which frequently had NOTCH1 mutations. In addition to T-ALL, TMD8 is another unique cell line sensitive to GSI, and is useful to study effects of GSI in molecular targeting therapy.

Topics: Adaptor Proteins, Signal Transducing; Amyloid Precursor Protein Secretases; Basic Helix-Loop-Helix Transcription Factors; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dipeptides; Enzyme Inhibitors; Fatal Outcome; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-2 Protein; Karyotyping; Ligands; Lymphoma, B-Cell; Male; Membrane Proteins; Middle Aged; Oligopeptides; Receptor, Notch1; Receptor, Notch2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Structure-Activity Relationship; Transcription Factor HES-1