Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Ungewickell, Alexander; Bhaduri, Aparna; Rios, Eon J.; Reuter, Jason; Lee, Carolyn; Mah, Angela; Zehnder, Ashley; Ohgami, Robert S.; Kulkarni, Shashikant; Armstrong, Randall; Weng, Wei; Gratzinger, Dita; Tavallaee, Mahkam; Rook, Alain H.; Snyder, M; Kim, Youn; Khavari, Paul A.

doi:10.1038/ng.3370

Cited by 249 publications

(288 citation statements)

References 30 publications

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“…Two other groups have recently reported the identification of the CTLA4-CD28 fusion gene in Sézary syndrome, an aggressive rare variant of cutaneous T-cell lymphoma. 25,26 That this mutation is not limited to Sézary syndrome but is found in a broad range of TCL types with an overall frequency of 30% and typically in combination with other mutations should be of significance.…”

Section: Discussionmentioning

confidence: 99%

Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

Yoo

Kim

et al. 2016

Haematologica

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Section: Discussionmentioning

confidence: 99%

Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

Yoo

Kim

et al. 2016

Haematologica

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“…13 In addition, amplifications and activating mutations in the CARD11 and the TNFRSF1B gene encoding the tumor necrosis factor receptor 2 (TNFR2) were identified in up to 30% of patients with high-stage CTCL. [14][15][16] These mutations cause constitutive signaling through the noncanonical NF-kB pathway in CTCL cells, further enhancing their cell death resistance.…”

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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“…[2][3][4][5][6][7][8] These studies have now confirmed, expanded, and functionally validated many of the genetic aberrations detected by aCGH in MF/SS, a broad and diverse spectrum that include genes associated with T-cell receptor (TCR) signaling, activation of NF-kB, JAK/STAT signaling, chromatin remodeling, and DNA damage response. However, despite a significant degree of overlap, there was great variability in the identity and frequency of alterations at putative driver genes across studies.…”

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confidence: 73%