Sézary syndrome: old enigmas, new targets

Nicolay, Jan P.; Felcht, Moritz; Schledzewski, Kai; Goerdt, Sergij; Géraud, Cyrill

doi:10.1111/ddg.12900

Cited by 29 publications

(35 citation statements)

References 109 publications

(131 reference statements)

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“…[5][6][7] It is, however, well-established that the malignant potential of CTCL depends on its distinct cell death resistance phenotype rather than on hyperproliferation. CTCL resistance toward cell death stimuli also complicates therapy because most cancer treatments aim at induction of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Nicolay

Müller‐Decker

Schroeder

et al. 2016

Blood

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Key Points• DMF induces specific cell death in CTCL cells and inhibits CTCL tumor growth and metastasis in vivo via inhibition of NF-kB.• DMF therefore represents a promising, nontoxic novel therapeutic approach to treating CTCL.Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-kB activation. Therefore, NF-kBdependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-kB-directed therapy would leave bystander T cells widely unaffected. We investigated the effects of dimethyl fumarate (DMF) on CTCL cells in vitro and in vivo. DMF induced cell death in primary patient-derived CD4 1 cells and CTCL cell lines, but hardly in T cells from healthy donors. DMF-induced cell death was linked specifically to NF-kB inhibition. To study the impact of DMF in vivo, we developed 2 CTCL xenograft mouse models with different cutaneous localizations of the T-cell infiltrate. DMF treatment delayed the growth of CTCL tumors and prevented formation of distant metastases. In addition, DMF induced increased cell death in primary CTCL tumors and in liver metastases. In summary, DMF treatment represents a remarkable therapeutic option in CTCL because it restores CTCL apoptosis in vitro and in preclinical models in vivo and prevents spreading of the disease to distant sites. DMF treatment is of particular promise in CTCL because DMF is already in successful clinical use in the treatment of psoriasis and multiple sclerosis allowing fast translation into clinical studies in CTCL. (Blood. 2016;128(6):805-815)

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Section: Introductionmentioning

confidence: 99%

Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

Nicolay

Müller‐Decker

Schroeder

et al. 2016

Blood

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“…Although consensus criteria for SS diagnosis and staging have been established (Olsen et al, 2007), the phenotype of Sézary cells is heterogeneous, because they may develop from naïve T cells, effector memory T cells, or central memory T cells, with differentiation plasticity mainly into T helper 2 (Th2) cells (Nicolay et al, 2016). The altered expressions of several biomarkers, including CD26 and/or CD7, in CD4 þ cells was confirmed as specific for SS diagnosis in a multicenter study (Boonk et al, 2016).…”

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confidence: 99%

“…represent innovative targets under evaluation (Duvic et al, 2015;Nicolay et al, 2016). Whether alterations of the genes encoding for PD1, CTLA-4, and CCR4 affect responses to these immune therapies has yet to be determined.…”

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confidence: 99%

Sézary Syndrome: Translating Genetic Diversity into Personalized Medicine

Chevret

Merlio

2016

Journal of Investigative Dermatology

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Sézary syndrome is probably the most studied cutaneous T-cell lymphoma subtype. Beyond the consensus criteria for Sézary syndrome diagnosis, Sézary cells display heterogeneous phenotypes and differentiation profiles. In the face of SS diversity, the great hope is to develop targeted therapies based on next-generation sequencing to define the genetic landscape of Sézary syndrome. Prasad et al. report on the use of exome sequencing and RNA sequencing to study selected CD4(+) blood cells from 15 patients with erythroderma Sézary syndrome, 14 of whom fulfilled the conventional criteria for diagnosis. The most common genetic abnormality, TP53 gene deletion on chromosome arm 17p and/or mutation, was observed in 58% of patients. However, mutations affecting PLCG1, STAT5B, GLI3, and CARD11 each were detected in only one individual. Nevertheless, Prasad et al. report single point mutations or copy number alterations in several new genes and in new fusion genes, with predicted biological relevance. This information underscores the diversity of genetic alterations and of the mechanisms of alterations of single genes. At the individual level, Sézary cells may combine alterations of genes involved in T-cell signaling, NF-kB and JAK-signal transducer and activator of transcription pathways, apoptosis control, chromatin remodeling, and DNA damage response. The therapeutic relevance of these potential targets needs to be evaluated with tests of function.

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“…The biology and pathogenesis of CL and especially CTCL have been investigated intensively (2). Two major challenges of CL treatment, however, remain unresolved.…”

Section: Introductionmentioning

confidence: 99%