Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma
- Maria R. Kamstrup1,*,
- Lise Mette Rahbek Gjerdrum2,
- Edyta Biskup1,
- Britt Thyssing Lauenborg3,
- Elisabeth Ralfkiaer2,
- Anders Woetmann3,
- Niels Ødum3, and
- Robert Gniadecki1
- 1 Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark;
- 2 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
- 3 Institute of Medical Microbiology and Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- * Corresponding author; email: mk43{at}bbh.regionh.dk
Abstract
Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signalling is involved in the pathogenesis of mycosis fungoides and Sezary syndrome, the most common subtypes of cutaneous T cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sezary 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 Sezary syndrome (SeAx, HuT-78)and in primary leukemic Sézary cells. Specific downregulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of NF-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.
- Submitted December 23, 2009.
- Accepted May 9, 2010.
- Copyright © 2005 American Society of Hematology
