Expression of <scp>FK</scp>506‐binding protein 51 (<scp>FKBP</scp>51) in Mycosis fungoides

Mascolo, Massimo; Romano, Maria Fiammetta; Ilardi, Gennaro; Romano, Simona; Baldo, Antonello; Scalvenzi, Massimiliano; Argenziano, Giuseppe; Merolla, Francesco; Russo, Daniela; Varricchio, Silvia; Pagliuca, Francesca; Russo, Marina; Ciancia, Giuseppe; Rosa, Gianluca De; Staibano, Stefania

doi:10.1111/jdv.14614

Cited by 7 publications

(4 citation statements)

References 70 publications

(148 reference statements)

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“…In MF and Sézary syndrome, NF‐κB can be activated upon TCR and tumour necrosis factor signalling pathway activation, and by structural alterations in the pathway components . Recently, it has been shown that FK506‐binding protein 51 and TAK1 (mitogen‐activated protein kinase kinase kinase 7) are involved in NF‐κB activation in CTCL . We detected variable nuclear expression levels of NF‐κB subunits (p50, p65, p52 and RelB).…”

Section: Discussionmentioning

confidence: 71%

“…8,11,12,20 Recently, it has been shown that FK506-binding protein 51 and TAK1 (mitogen-activated protein kinase kinase kinase 7) are involved in NF-jB activation in CTCL. 21,22 We detected variable nuclear expression levels of NF-jB subunits (p50, p65, p52 and RelB). p50 and p52 were both detected in T-cell nuclei in around 50% of cases, while p65 and RelB were found in 25%.…”

Section: Discussionmentioning

confidence: 92%

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Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways

Pérez

Mondéjar

García-Díaz

et al. 2020

British Journal of Dermatology

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Summary Background The malignant mechanisms that control the development of cutaneous T‐cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS–mitogen‐activated protein kinase, T‐cell receptor (TCR)–phospholipase C gamma 1 (PLCG1)–nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)–signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. Objectives To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. Methods We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin‐fixed paraffin‐embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR–PLCG1–NFAT, JAK–STAT and NF‐κB pathways. Folliculotropism and large‐cell transformation were also examined. Results NFAT and nuclear factor kappa B (NF‐κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large‐cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF‐negative cases. A significant association of NFAT with NF‐κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T‐cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell‐survival pathways. A higher mutational allele frequency was detected in advanced stages. Conclusions Our results show that STAT3 is activated in advanced cases and is associated with large‐cell transformation, while the activation of NFAT and NF‐κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large‐cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T‐cell lymphoma‐associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in ...

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways

Pérez

Mondéjar

García-Díaz

et al. 2020

British Journal of Dermatology

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“…Then 4-mm-thick formalin-fixed, paraffin-embedded sections were stained with hematoxylin and eosin. Immunohistochemistry was performed as previously described 21 with anti-CD3 and anti-CD31 antibodies to highlight the lymphocytic infiltrate and the endothelium, respectively.…”

Section: Macroscopic (Clinical and Dermoscopic) And Microscopic (Histopathologic) Analysismentioning

confidence: 99%

Bilateral Chilblain-like Lesions of the Toes Characterized by Microvascular Remodeling in Adolescents During the COVID-19 Pandemic

et al. 2021

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IMPORTANCE Chilblain-like lesions have been one of the most frequently described cutaneous manifestations during the COVID-19 pandemic. Their etiopathogenesis, including the role of SARS-CoV-2, remains elusive. OBJECTIVE To examine the association of chilblain-like lesions with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS This prospective case series enrolled 17 adolescents who presented with chilblain-like lesions from April 1 to June 30, 2020, at a tertiary referral academic hospital in Italy. MAIN OUTCOMES AND MEASURES Macroscopic (clinical and dermoscopic) and microscopic (histopathologic) analysis contributed to a thorough understanding of the lesions. Nasopharyngeal swab, serologic testing, and in situ hybridization of the skin biopsy specimens were performed to test for SARS-CoV-2 infection. Laboratory tests explored signs of systemic inflammation or thrombophilia. Structural changes in peripheral microcirculation were investigated by capillaroscopy. RESULTS Of the 17 adolescents (9 [52.9%] male; median [interquartile range] age, 13.2 [12.5-14.3] years) enrolled during the first wave of the COVID-19 pandemic, 16 (94.1%) had bilaterally localized distal erythematous or cyanotic lesions. A triad of red dots (16 [100%]), white rosettes (11 [68.8%]), and white streaks (10 [62.5%]) characterized the dermoscopic picture. Histologic analysis revealed a remodeling of the dermal blood vessels with a lobular arrangement, wall thickening, and a mild perivascular lymphocytic infiltrate. SARS-CoV-2 infection was excluded by molecular and serologic testing. In situ hybridization did not highlight the viral genome in the lesions. CONCLUSIONS AND RELEVANCEThis study delineated the clinical, histologic, and laboratory features of chilblain-like lesions that emerged during the COVID-19 pandemic, and its findings do not support their association with SARS-CoV-2 infection. The lesions occurred in otherwise healthy adolescents, had a long but benign course to self-resolution, and were characterized by a microvascular remodeling with perivascular lymphocytic infiltrate but no other signs of vasculitis.These results suggest that chilblain-like lesions do not imply a concomitant SARS-CoV-2 infection.Ongoing studies will help clarify the etiopathogenic mechanisms.

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“…advanced stages (IIB-IVB), the 10-year survival decreases to less than 40% [9,10]. Few MF cases may undergo large cell transformation, characterized by an aggressive clinical course and a median survival of less than 2 years [11].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Role of chromatin assembly factor-1/p60 and poly [ADP-ribose] polymerase 1 in mycosis fungoides

et al. 2020

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Mycosis fungoides (MF) represents the most common type of cutaneous lymphoma. In the majority of patients, the disease has a slow evolution and a protracted course; however, a subset of patients shows poor oncologic outcomes. Unfortunately, there are no reliable prognostic markers for MF, and the currently available treatments are only effective in a minority of patients. This study aimed to evaluate the expression and clinical significance of PARP-1 and CAF-1/p60 in MF. Sixty-four MF representatives of the different stages of disease were assessed by immunohistochemistry for PARP-1 and CAF-1/p60. The association of PARP-1 and CAF-1/p60 with the MF stage and outcome was assessed by using Fisher’s exact test and Kaplan-Meier survival analysis with the Log-rank test; a p value < 0.05 was considered significant. PARP-1 was overexpressed in 57.9% of MF and was significantly associated with a MF stage > II (p = 0.034) but not with the risk of death (p = 0.237). CAF-1/p60 was overexpressed in 26.8% of MF and was significantly associated with decreased overall survival (p < 0.001) but not with the MF stage (p = 1). A significant association was found between PARP-1 overexpression and CAF-1/p60 overexpression (p = 0.0025). Simultaneous overexpression of PARP-1 and CAF-1/p60 was significantly associated with decreased overall survival (p < 0.001), although less strongly than CAF-1/p60 alone (χ2 = 14.916 vs 21.729, respectively). In MF, PARP-1 is overexpressed in advanced stages, while CAF-1/p60 is overexpressed in the cases with shorter overall survival, appearing as a significant prognostic marker. A role for PARP-1 inhibitors and anti-CAF-1/p60 targeted therapy may be reasonably hypothesized in MF.

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Expression of FK506‐binding protein 51 (FKBP51) in Mycosis fungoides

Abstract: We hypothesize a role for FKBP51 as a prognostic marker for MF and suggest an involvement of this immunophilin in deregulated NF-κB pathway of this CTCL.

Cited by 7 publications

References 70 publications

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways

Bilateral Chilblain-like Lesions of the Toes Characterized by Microvascular Remodeling in Adolescents During the COVID-19 Pandemic

Role of chromatin assembly factor-1/p60 and poly [ADP-ribose] polymerase 1 in mycosis fungoides

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