Notch1 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 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.

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

“…19 The ability of GSI I to target Notch, AKT and other pro-survival pathways, has also been shown in cutaneous T-cell lymphoma. 50 All these findings have led to an in-depth understanding of the mechanisms of action of GSI I in tumor cells which is essential to define the potential clinical use of GSI I.…”

Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma

“…Aberrations in signal transducers and transcription factors have been reported in SS studies, such as Jun B, JunD, TGFBR2, STAT3, STAT4, CDKN1C, CTLA-4, GATA3, AHI-1, SATB1, PDCD10, and NOTCH1. 4,16,17,[32][33][34][35][36] Several of these dysregulated genes (TGFBR2, GATA3, STAT3, SATB1, and NOTCH1) are involved in the signal cascades governing T-cell development. [37][38][39][40][41] Our recent observation of aberrant TOX upregulation in MF, subsequently confirmed by McGirt et al, 10 prompted us to ask whether TOX is also upregulated in SS, the advanced CTCL, and whether TOX contributes to the development of CTCL.…”

Transcriptome sequencing in Sézary syndrome identifies Sézary cell and mycosis fungoides-associated lncRNAs and novel transcripts

“…Presenilin-1 is part of the ␥-secretase complex that activates Notch1, a potential therapeutic target in CTCL and an important oncogenic pathway in T-cell acute lymphoblastic leukemia. 43 KCNN4 is a calcium-regulated potassium channel implicated in T-cell activation and proliferation; inhibition of this channel by TRAM-34 decreases inflammation in murine models of encephalomyelitis and colitis, 44 raising the possibility that it may also reduce SC proliferation. We further note overexpression of PDCD1 in SCs, consistent with previous reports.…”