Notch1 as a potential therapeutic target in cutaneous T-cell lymphoma

• Published in: Blood 2010-10, Vol.116 (14), p.2504-2512
• Main Authors: Kamstrup, Maria R., Gjerdrum, Lise Mette Rahbek, Biskup, Edyta, Thyssing Lauenborg, Britt, Ralfkiaer, Elisabeth, Woetmann, Anders, Ødum, Niels, Gniadecki, Robert
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Female; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Lymphocytes - metabolism; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - metabolism; Lymphoma, T-Cell, Cutaneous - pathology; Male; Medical sciences; Middle Aged; Mycosis Fungoides - drug therapy; Mycosis Fungoides - genetics; Mycosis Fungoides - metabolism; Mycosis Fungoides - pathology; NF-kappa B - metabolism; Protease Inhibitors - pharmacology; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; RNA Interference; Sezary Syndrome - drug therapy; Sezary Syndrome - genetics; Sezary Syndrome - metabolism; Sezary Syndrome - pathology; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-12-260216

Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signaling is involved in the pathogenesis of mycosis fungoides and Sézary syndrome, the most common subtypes of cutaneous T-cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sézary syndrome, we demonstrated prominent expression of Notch1 on tumor cells, especially in the more advanced stages. The γ-secretase inhibitor I blocked Notch signaling and potently induced apoptosis in cell lines derived from mycosis fungoides (MyLa) and Sézary syndrome (SeAx, HuT-78) and in primary leukemic Sézary cells. Specific down-regulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of nuclear factor-κB, which is the most important prosurvival pathway in cutaneous T-cell lymphoma. Our data show that Notch is present in cutaneous T-cell lymphoma and that its inhibition may provide a new way to treat cutaneous T-cell lymphoma.