RESUMO
Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/fisiologia , PTEN Fosfo-Hidrolase/fisiologia , Síndrome de Sézary/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 10/ultraestrutura , Metilação de DNA , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Deleção de Genes , Dosagem de Genes , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Análise de Sequência de DNA , Síndrome de Sézary/genética , Transdução de Sinais , Pele/metabolismo , Pele/patologiaAssuntos
Carcinoma/complicações , Epidermólise Bolhosa Adquirida/etiologia , Síndromes Paraneoplásicas/etiologia , Pele/patologia , Neoplasias da Glândula Tireoide/complicações , Biomarcadores Tumorais/análise , Biópsia , Carcinoma/diagnóstico , Carcinoma/imunologia , Carcinoma/terapia , Carcinoma Papilar , Epidermólise Bolhosa Adquirida/diagnóstico , Epidermólise Bolhosa Adquirida/imunologia , Epidermólise Bolhosa Adquirida/terapia , Glucocorticoides/uso terapêutico , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/imunologia , Síndromes Paraneoplásicas/terapia , Compostos Radiofarmacêuticos/uso terapêutico , Indução de Remissão , Pele/efeitos dos fármacos , Pele/imunologia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Sézary syndrome is a rare and very aggressive leukemic variant of cutaneous T-cell lymphoma characterized by extensive skin involvement and a malignant circulating CD4(+) T-cell clone which homes to the skin, over-expresses CD60, and lacks CD7, CD26 and CD49d. So far prognostic markers in this disease are limited to treatment with systemic steroids, age, serum lactate dehydrogenase, and a white blood cell count of 20×10(9)/L or higher: no other biological marker with prognostic value, especially related to malignant cells, has been described. DESIGN AND METHODS: We used flow activated cell sorting analysis to compare the distribution of the T-cell receptor-Vß repertoire and several surface molecules (CD7, CD26, CD49d and CD60) within the circulating CD4(+) T-cell population in 62 patients with Sézary syndrome, 180 with mycosis fungoides, 6 with B-cell lymphomas, and 19 with chronic eczema. We calculated the 5-year overall survival of patients with Sézary syndrome after first hospital admission using Kaplan-Meier product-limit estimates and hazard ratios from the Cox proportional hazards model. RESULTS: We found that both higher number of CD60(+) and lower number of CD49d(+) cells within circulating CD4(+) T cells at disease presentation were significantly associated with a lower probability of survival. An exceedingly high risk of death was observed for patients with a combination of a high proportion of CD4(+)CD60(+) cells (≥ 0.5×10(9)/L) and low proportion of CD4(+)CD49d(+) cells (<0.5×10(9)/L) (hazard ratio = 12.303, 95% confidence interval 1.5-95.9; P<0.02). In addition, a skewed usage of T-cell receptor-Vß subfamilies was observed in the circulating T-cell clone for 61.9% of all patients with Sézary syndrome, T-cell receptor-Vß 2 and 5.1 subfamilies being the most frequently represented (42.8%), followed by T-cell receptor-Vß 12 and 13.1. CONCLUSIONS: In this study we showed that up-regulation of CD60 and down-regulation of CD49d on circulating CD4(+) T cells are two useful markers for predicting a very poor outcome in patients with Sézary syndrome.
Assuntos
Biomarcadores Tumorais/sangue , Linfócitos T CD4-Positivos/metabolismo , Gangliosídeos/sangue , Integrina alfa4/sangue , Síndrome de Sézary , Neoplasias Cutâneas , Adulto , Idoso , Antígenos CD7/sangue , Dipeptidil Peptidase 4/sangue , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Síndrome de Sézary/sangue , Síndrome de Sézary/mortalidade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Taxa de SobrevidaRESUMO
A descriptive study in a Dermatological Research Institution in Rome, Italy, was conducted to test the feasibility and acceptability of health related quality of life (HRQoL) assessment in the daily routine. Quality of life, and psychosocial distress evaluations were obtained for each patient. Patients were invited to complete the Skindex-29, GHQ-12, and SF-36. Results were returned to the clinical staff using standardised feed-back forms with: a) "categories" of QoL scores to help interpreting Skindex-29 scores; b) "warnings" pointing out problems that patients experienced "all the time"; c) categories of GHQ-12 scores for minor psychiatric problems; d) the classical SF-36 graph depicting the patient's "QoL profile" with normative references. The clinical staff were trained, and then their attitudes and behaviours were surveyed using a standardised questionnaire. For all 170 participants enrolled (63% males, 35% age > 64 years), feed-back forms were provided within three hours from data collection. For patients with repeated hospitalisations time-trends in HRQoL measurements were also provided. The acceptability, both for patients and the clinical staff, was high but the actual impact on clinical activities was limited. The routine assessment of HRQoL in dermatology is feasible and well accepted both by patients and by the clinical staff. The application of these widely used questionnaires should be implemented in a larger scale and evaluated in different settings.
Assuntos
Qualidade de Vida , Dermatopatias , Inquéritos e Questionários , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dermatopatias/complicações , Dermatopatias/diagnóstico , Dermatopatias/psicologiaRESUMO
In this study, we used single nucleotide polymorphism and comparative genomic hybridization array to study DNA copy number changes and loss of heterozygosity for 28 patients affected by Sézary syndrome (SS), a rare form of cutaneous T-cell lymphoma (CTCL). Our data identified, further confirming previous studies, recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71% and 68% of cases, respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in >30% of tumors: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. Individual chromosomal aberrations did not show a significant correlation with prognosis; however, when more than three recurrent chromosomal alterations (gain or loss) were considered, a statistical association was observed using Kaplan-Meier survival analysis. Integrating mapping and transcriptional data, we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer-related genes such as members of the NF-kappaB pathway (BAG4, BTRC, NKIRAS2, PSMD3, and TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times, we identify several common candidates that might exert critical roles in SS, such as BUB3 and PIP5K1B. Altogether, our study confirms and maps more precisely the regions of gain and loss and, combined to transcriptional profiles, suggests a novel set of genes of potential interest in SS.
Assuntos
Aberrações Cromossômicas , Dosagem de Genes , Perfilação da Expressão Gênica , Perda de Heterozigosidade , Proteínas de Neoplasias/genética , Síndrome de Sézary/genética , Síndrome de Sézary/patologia , Cromossomos Humanos/genética , Hibridização Genômica Comparativa , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
Chemokine and chemokine receptors expressed by normal and neoplastic lymphocytes play a key role in cell recruitment into skin and lymph nodes. The aim of this study was to get further insights into the role of chemokines in pathogenesis and progression of cutaneous T-cell lymphoma (CTCL) with particular regard to Sézary Syndrome (SS), a CTCL variant with blood involvement. Here, we show that functional CXCL13 homeostatic chemokine is strongly up-regulated in SS cells, well-detectable in skin lesions and lymph nodes, and measurable at high concentration in plasma of SS patients, at different levels during disease progression. Furthermore, we show that the addition of CXCL13 to CCL19 or to CCL21, the selective CCR7 agonists responsible for lymph node homing, strongly enhances the migration of CCR7+ SS cells. We also show that neutralization of the CCR7 receptor strongly impairs CCL19/21-induced chemotaxis of SS cells both in the absence or presence of CXCL13. Additional experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of SS cells. Our findings suggest that this newly described CXCL13 expression in SS represents a new pathogenetic mechanism of diagnostic significance.
Assuntos
Movimento Celular/fisiologia , Quimiocina CCL19/fisiologia , Quimiocina CCL21/fisiologia , Quimiocina CXCL13/biossíntese , Síndrome de Sézary/metabolismo , Idoso , Estudos de Casos e Controles , Adesão Celular , Linhagem Celular , Quimiotaxia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome de Sézary/patologiaRESUMO
Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma (CTCL) characterized by a distinct metastatic pattern mainly involving blood and skin. Chemokines and their receptors play a critical role in cellular recruitment and homing to tissues and in the metastatic process of several tumors including non-Hodgkin T-cell lymphomas (NHLs). Here we report that SS cells express a functionally active CXCR4 and that its ligand SDF-1 is abundantly produced in the skin, which represents the main destination of SS cell spreading. SDF-1 is normally inactivated by proteolytic cleavage by the CD26/dipeptidylpeptidase IV (DPPIV). The lack of CD26 from the cell surface is a hallmark of circulating SS cells. We also show that the CD26(-) phenotype is maintained also in skin-infiltrating neoplastic T lymphocytes and that SS-affected individuals exhibit a reduced activity of plasma soluble CD26. Finally, we observe that the addition of soluble CD26 reduces the migratory response of SS cells to SDF-1 whereas the inhibition of the CD26 peptidase activity in Hut78, a CD26(+) CTCL cell line, enhances the SDF-1-induced migration of these cells. Our findings suggest that the SDF-1-CXCR4 axis could play an important role in skin homing of SS through the regulatory activity of CD26.