NOTCH1 signaling as a therapeutic target in Sézary syndrome.
NOTCH signaling is important for development and tissue homeostasis and is activated in many human cancers. We investigated a role for NOTCH1 signaling in Sézary syndrome (SS), a cutaneous T-cell lymphoma in which CD4+ tumor cells (Sézary cells) are present in the skin, lymph nodes, and peripheral blood. We show consistent expression of activated NOTCH1 by Sézary cells isolated from peripheral blood of SS patients, as well as the SS-derived cell lines SeAx and HuT78. In addition, immunohistochemical stainings of skin biopsies from SS patients showed consistent expression of nuclear NOTCH1 and its downstream target hairy/enhancer of split-1 (HES1) by Sézary cells. We demonstrate that this persistent NOTCH1 activation is not caused by mutations in the coding regions of NOTCH1 and F-box and WD40 domain protein 7 (FBWX7) genes. Inhibition of NOTCH1 signaling by gamma secretase inhibitors decreased cellular viability and induced apoptosis of Sézary cells. These observations argue that NOTCH1 signaling is functionally involved in the pathogenesis of SS, and inhibition of NOTCH1 signaling represents a new therapeutic target for the treatment of SS.
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Leslie
L
van der Fits
Yongjun
Y
Qin
Jacoba J
JJ
Out-Luiting
Kim G
KG
Vermeer
Sean
S
Whittaker
Johan H
JH
van Es
Cornelis P
CP
Tensen
Maarten H
MH
Vermeer
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001570:Benzodiazepinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012751:Sezary Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D001570:Benzodiazepinones; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D018398:Homeodomain Proteins; D009842:Oligopeptides; D051059:PTEN Phosphohydrolase; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases; C576532:2-(2-(3,5-difluorophenyl)-acetylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propionamide; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; C494086:STAT3 protein, human; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; C078493:HES1 protein, human; C494929:PTEN protein, human