ABSTRACT
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bortezomib/pharmacology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Multiple Myeloma/drug therapy , Pyrazoles/pharmacology , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Cycle/drug effects , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Coculture Techniques , Dose-Response Relationship, Drug , Female , Gene Expression Regulation, Neoplastic , Humans , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Lenalidomide , Male , Middle Aged , Multiple Myeloma/enzymology , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Nitriles , Pyrimidines , Stromal Cells/drug effects , Stromal Cells/metabolism , Stromal Cells/pathology , Thalidomide/pharmacology , Time FactorsABSTRACT
The aim of the present study was to determine whether there is an association between serum free light chains (sFLC) quantification and the development of post-transplant lymphoproliferative disorder (PTLD), using serum samples from a nested case-control cohort of patients with renal transplant. Ten new cases of PTLD and 46 controls were enrolled. Additional comparison groups consisted of five human immunodeficiency virus (HIV)-infected individuals, five with untreated Hodgkin lymphoma and six normal individuals. Serum κ and λ FLC concentrations were measured by nephelometry and compared with reference ranges (normal and renal ranges). κ and/or λ were above the normal range in 90% of cases and in 65% of matched controls. There was no statistically significant difference between all groups, except for λ FLC concentrations between cases of PTLD and normal individuals (p = 0.016). The κ/λ sFLC ratios of cases and controls were within the renal range and normal range. Our results suggest that sFLC are not useful to predict PTLD development in renal transplant recipients.
Subject(s)
Immunoglobulin Light Chains/blood , Kidney Transplantation , Lymphoma/blood , Lymphoma/etiology , Adult , Case-Control Studies , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/complications , Female , HIV Infections/blood , HIV Infections/complications , Hodgkin Disease/blood , Hodgkin Disease/etiology , Humans , Immunoglobulin kappa-Chains/blood , Immunoglobulin lambda-Chains/blood , Kidney Function Tests , Kidney Transplantation/adverse effects , Male , Middle Aged , Young AdultABSTRACT
The exact function of MAGE-C1/CT7 and MAGE-C2/CT10 is not yet understood in multiple myeloma (MM). However, the homologs MAGE-C1/CT7 and MAGE-C2/CT10 genes encode highly immunogeneic cancer/testis antigens (CTAs) and can be potential targets for T cell-based immunotherapy. MAGE-C1/CT7 and MAGE-C2/CT10 mRNA expression were investigated in MM patients, solitary plasmacytomas, monoclonal gammopathies of undetermined significance (MGUS) and bone marrow (BM) aspirates from healthy donors by RT-PCR. MAGE-C1/CT7 and MAGE-C1/CT10 were expressed in 67 and 59 % of the 46 MM analyzed patients. At least one of the genes was expressed in 76 % of MM cases. Solitary plasmacytoma also showed MAGE-C1/CT7 and MAGE-C2/CT10 expression. MAGE-C1/CT7 and MAGE-C2/CT10 were not expressed in normal BM samples, showing restricted expression of these CTA genes in MM, solitary plasmacytoma and MGUS. In the present study, we found high expression of the homologs MAGE-C1/CT7 and MAGE-C2/CT10 in monoclonal gammopathies and speculate whether these genes might represent a valuable therapeutic option for myeloma, in particular for combined immunotherapy.
Subject(s)
Antigens, Neoplasm/biosynthesis , Gene Expression Regulation , Immunotherapy , Multiple Myeloma/metabolism , Multiple Myeloma/therapy , Neoplasm Proteins/biosynthesis , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/analysis , Biomarkers/analysis , Female , Humans , Male , Middle Aged , Multiple Myeloma/immunology , Neoplasm Proteins/analysis , Reverse Transcriptase Polymerase Chain Reaction , TranscriptomeABSTRACT
The development of multiple myeloma (MM) involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4(+) and CD8(+) T cells have been described in MM. The balance between T regulatory cells (Treg) and T helper (Th) 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-ß and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.
