RESUMO
Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n=6) and flow cytometry on cell suspensions (n=4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma de Células T Periférico/enzimologia , Proteínas Tirosina Quinases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 9/genética , Feminino , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Imunofenotipagem , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma Extranodal de Células T-NK/enzimologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Cutâneo de Células T/enzimologia , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Proteínas Tirosina Quinases/genética , Quinase Syk , Translocação Genética , Tirosina/metabolismoAssuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Isocitrato Desidrogenase/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Polimorfismo Genético/genética , Alelos , Genótipo , Glioma/genética , Humanos , RNA Longo não Codificante , Fatores de RiscoRESUMO
BACKGROUND: We conducted a phase I clinical immunotherapy trial of CML to evaluate the safety of a clinical-grade leukemic DC product standardized for purity and mature phenotype. METHODS: We injected autologous DC into patients in late chronic or accelerated phases of CML. The patients received mature CD83+ and bcr-abl+ DC prepared from CD14+ cells. Two cohorts of three patients received four injections each of 3 x 10(6) DC and 15 x 10(6) DC/injection, respectively. The first patient was studied before imatinib mesylate (IM) was available, four patients were treated concurrently with IM therapy and one did not tolerate the IM and was off the drug at the time of DC therapy. IM effects on WBC counts precluded DC preparation in numbers sufficient for further dose escalation. The first patient received DC s.c. and all subsequent patients received DC into a cervical lymph node under ultrasound guidance. RESULTS: DC injections were well tolerated. We observed no clinical responses. T cells drawn later in the course of therapy were more sensitive to stimulation by CML DC in vitro. DISCUSSION: The increase in T-cell sensitivity to CML-specific stimulation that accompanied active immunization by CML DC justifies further clinical studies, possibly with modifications such as an increased frequency and number of DC injections.
Assuntos
Células Dendríticas/transplante , Imunoterapia Ativa/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Idoso , Antígenos CD/análise , Antígeno B7-2/análise , Células da Medula Óssea/citologia , Contagem de Células , Proliferação de Células , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Proteínas de Fusão bcr-abl/análise , Humanos , Imunoglobulinas/análise , Imunoterapia Ativa/efeitos adversos , Interferon gama/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucócitos Mononucleares/citologia , Receptores de Lipopolissacarídeos/análise , Ativação Linfocitária/imunologia , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/transplante , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Autólogo , Resultado do Tratamento , Antígeno CD83RESUMO
Translocations involving IGH are common in some lymphoid malignancies but are believed to be rare in chronic lymphocytic leukaemia (CLL). To study the clinical utility of fluorescence in situ hybridization (FISH) for IGH translocations, we reviewed 1032 patients with a presumptive diagnosis of CLL. Seventy-six (7%) patients had IGH translocations. Pathology and clinical data were available for the 24 patients evaluated at the Mayo Clinic. Ten (42%) patients had IGH/cyclin D1 fusion and were diagnosed with mantle cell lymphoma (MCL). The immunophenotype was typical of MCL in three of these patients and atypical for MCL in seven patients. One patient had biclonal disease with typical MCL and CLL with IGH/BCL-2. Eleven (46%) patients had IGH/BCL-2 fusion including the patient with biclonal disease. Two of these patients had leukaemic phase follicular lymphoma and nine patients had CLL. The median progression-free survival of patients with CLL and IGH/BCL-2 translocation was 20.6 months. The two patients with IGH/BCL-3 fusion (one of these also had IGH/BCL-11a) had rapid disease progression. The IGH partner gene was not identified in two patients. We conclude that use of an IGH probe in FISH analysis of monoclonal B-cell lymphocytosis improves diagnostic precision and could have prognostic value in patients with CLL.