ABSTRACT
Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , Boronic Acids/pharmacology , Lymphoma, Mantle-Cell/drug therapy , Pyrazines/pharmacology , Thalidomide/analogs & derivatives , Animals , Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Bortezomib , Cell Differentiation , Cell Line, Tumor , Drug Screening Assays, Antitumor , Drug Synergism , Gene Expression Profiling , Humans , Interferon Regulatory Factors/metabolism , Lenalidomide , Mice , Mice, SCID , Neoplasm Transplantation , Proteasome Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-myc/metabolism , Pyrazines/therapeutic use , Signal Transduction , Thalidomide/pharmacology , Thalidomide/therapeutic useSubject(s)
Benzenesulfonates/pharmacology , Cell Movement/drug effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Receptors, Antigen, B-Cell/antagonists & inhibitors , Tumor Microenvironment/drug effects , Blotting, Western , Cell Survival , Chemokines/metabolism , Chemotaxis/drug effects , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/metabolism , Sorafenib , Syk Kinase , Tumor Cells, Cultured , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/genetics , src-Family Kinases/metabolismABSTRACT
CD38, a nucleotide-metabolizing ectoenzyme and a receptor, is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients. CD38 has a genetic polymorphism, with a C â G variation in a putative E-box located in a regulatory region. E2A, the predominant E-box factor in B lymphocytes, was found to be highly expressed by CD38(+) CLL patients. The highest CD38 levels scored by E2A(+)/G carrier patients suggested that E2A is (i) directly associated with CD38 expression, and that (ii) the binding of the transcription factor is influenced by the CD38 genotype. Chromatin immunoprecipitation indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, E2A binding was stronger in the presence of the G allele. Experiments of E2A silencing led to a significant reduction of surface levels of CD38, confirming the working hypothesis. A direct functional interplay between E2A and CD38 was shown by exposing CLL cells to interleukin-2 and TLR-9 ligands, both inducers of CD38 expression. Under these conditions, CD38 upregulation was primarily conditioned by the presence of E2A and then by the G allele. The results of this study link E2A and CD38 expression within a common pathway, in which E-protein activity is required for the efficient induction of CD38 transcription.
Subject(s)
ADP-ribosyl Cyclase 1/genetics , Basic Helix-Loop-Helix Transcription Factors/physiology , Gene Expression Regulation, Leukemic , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Membrane Glycoproteins/genetics , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Cells, Cultured , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Transcription, GeneticABSTRACT
Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.
