Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma

Maria Rørbæk Kamstrup; Lise Mette Rahbek Gjerdrum; Edyta Urszula Biskup; Britt Thyssing Lauenborg; Elisabeth Methner Ralfkiær; Anders Woetmann Andersen; Niels Ødum; Robert Gniadecki

doi:10.1182/blood-2009-12-260216

Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma

Maria Rørbæk Kamstrup, Lise Mette Rahbek Gjerdrum, Edyta Urszula Biskup, Britt Thyssing Lauenborg, Elisabeth Methner Ralfkiær, Anders Woetmann Andersen, Niels Ødum, Robert Gniadecki

61 Citations (Scopus)

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 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.

Original language	English
Journal	Blood
Volume	116
Issue number	14
Pages (from-to)	2504-12
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2009-12-260216
Publication status	Published - 7 Oct 2010

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10.1182/blood-2009-12-260216

http://www.bloodjournal.org/content/116/14/2504.full.pdf

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@article{338f5280c55f11df825b000ea68e967b,

title = "Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma",

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 signaling is involved in the pathogenesis of mycosis fungoides and S{\'e}zary syndrome, the most common subtypes of cutaneous T-cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and S{\'e}zary 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 S{\'e}zary syndrome (SeAx, HuT-78) and in primary leukemic S{\'e}zary 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.",

author = "Kamstrup, {Maria R{\o}rb{\ae}k} and Gjerdrum, {Lise Mette Rahbek} and Biskup, {Edyta Urszula} and Lauenborg, {Britt Thyssing} and Ralfki{\ae}r, {Elisabeth Methner} and Andersen, {Anders Woetmann} and Niels {\O}dum and Robert Gniadecki",

year = "2010",

month = oct,

day = "7",

doi = "10.1182/blood-2009-12-260216",

language = "English",

volume = "116",

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journal = "Blood",

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publisher = "American Society of Hematology",

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T1 - Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma

AU - Kamstrup, Maria Rørbæk

AU - Gjerdrum, Lise Mette Rahbek

AU - Biskup, Edyta Urszula

AU - Lauenborg, Britt Thyssing

AU - Ralfkiær, Elisabeth Methner

AU - Andersen, Anders Woetmann

AU - Ødum, Niels

AU - Gniadecki, Robert

PY - 2010/10/7

Y1 - 2010/10/7

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2009-12-260216

DO - 10.1182/blood-2009-12-260216

M3 - Journal article

C2 - 20538790

SN - 0006-4971

VL - 116

SP - 2504

EP - 2512

JO - Blood

JF - Blood

IS - 14

ER -

Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma

Abstract

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