Notch1 as a potential therapeutic target in cutaneous T-cell lymphoma.
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.
Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark. mk43@bbh.regionh.dk
Maria R
MR
Kamstrup
Lise Mette Rahbek
LM
Gjerdrum
Edyta
E
Biskup
Britt Thyssing
BT
Lauenborg
Elisabeth
E
Ralfkiaer
Anders
A
Woetmann
Niels
N
Ødum
Robert
R
Gniadecki
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012751:Sezary Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases