Subject(s)
Intracellular Signaling Peptides and Proteins/genetics , Isocitrate Dehydrogenase/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Acute/genetics , Mutation/genetics , Polymorphism, Genetic/genetics , Alleles , Genotype , Glioma/genetics , Humans , RNA, Long Noncoding , Risk FactorsABSTRACT
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.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Lymphoma, T-Cell, Peripheral/enzymology , Protein-Tyrosine Kinases/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Blotting, Western , Child , Child, Preschool , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 9/genetics , Female , Flow Cytometry , Humans , Immunoenzyme Techniques , Immunophenotyping , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins/genetics , Lymphoma, Extranodal NK-T-Cell/enzymology , Lymphoma, Extranodal NK-T-Cell/genetics , Lymphoma, Extranodal NK-T-Cell/pathology , Lymphoma, Large-Cell, Anaplastic/enzymology , Lymphoma, Large-Cell, Anaplastic/genetics , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, T-Cell, Cutaneous/enzymology , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell, Peripheral/pathology , Male , Middle Aged , Phosphorylation , Protein-Tyrosine Kinases/genetics , Syk Kinase , Translocation, Genetic , Tyrosine/metabolismABSTRACT
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.
Subject(s)
Dendritic Cells/transplantation , Immunotherapy, Active/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Aged , Antigens, CD/analysis , B7-2 Antigen/analysis , Bone Marrow Cells/cytology , Cell Count , Cell Proliferation , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Fusion Proteins, bcr-abl/analysis , Humans , Immunoglobulins/analysis , Immunotherapy, Active/adverse effects , Interferon-gamma/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Leukocytes, Mononuclear/cytology , Lipopolysaccharide Receptors/analysis , Lymphocyte Activation/immunology , Male , Membrane Glycoproteins/analysis , Middle Aged , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/transplantation , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transplantation, Autologous , Treatment Outcome , CD83 AntigenABSTRACT
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.
