ABSTRACT
Cyclin D1 (CCND1) overexpression is an early and unifying oncogenic event in mantle cell lymphoma (MCL) and multiple myeloma (MM) with chromosome 11q13 abnormalities. Herein, we report newly discovered transcript variants of the CCND1 gene in MCL and MM cells with chromosome 11q13 abnormalities. These transcript variants, designated CCND1.tv., covered the full-length coding region of CCND1 with longer 5'-untranslated regions (5'-UTRs) of CCND1 and occasionally contained a novel exon. CCND1.tv. was specifically detectable in patient-derived primary MCL or MM cells with chromosomal translocation t(11;14)(q13;q32), but not in t(11;14)-negative cells. The lengths of the 5'-UTR sequences of CCND1.tv. differed among patients and cell lines. Introduction of CCND1.tv. led to increased expression of normal-sized CCND1 protein in HEK293 cells. Furthermore, mTOR inhibition by rapamycin or serum starvation reduced ectopic expression of CCND1.tv.-derived CCND1 protein, but not 5'-UTR less CCND1-derived CCND1 protein in HEK293 cells, suggesting that the protein expression of CCND1.tv. is regulated by the mTOR pathway. Our results suggest that the aberrant expression of CCND1.tv. may contribute to the understanding of the pathogenesis of MCL and MM with 11q13 abnormalities.
Subject(s)
Chromosomes, Human, Pair 11 , Cyclin D1 , Gene Expression Regulation, Neoplastic , Lymphoma, Mantle-Cell , Multiple Myeloma , Transcription, Genetic , Translocation, Genetic , 5' Untranslated Regions , Cell Line, Tumor , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 11/metabolism , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 14/metabolism , Cyclin D1/biosynthesis , Cyclin D1/genetics , Exons , HEK293 Cells , Humans , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: Since bromodomain-containing protein 4 (BRD4) facilitates the transcription of genes important for neoplastic cells in a cancer-type specific manner, BRD4-regulated molecules may also include therapeutic targets for mantle cell lymphoma (MCL), a treatment-refractory subtype of malignant lymphoma. MATERIALS AND METHODS: In order to uncover direct BRD4-regulated targets in MCL, we performed integrated analysis using the pathway database and the results of both gene-expression profiling and chromatin immunoprecipitation with parallel sequencing for BRD4. RESULTS: Treatment with BRD4 inhibitor I-BET151 exerted a dose-dependent inhibitory effect on cell proliferation in MCL cell lines. BRD4 was found to directly regulate series of genes involved in the B-cell receptor (BCR) signaling pathway, including B-cell linker (BLNK), paired box 5 (PAX5), and IKAROS family zinc finger 3 (IKZF3), and several oncogenes, such as MYB. Indeed, the combinatory inhibition of BCR pathway and IKZF showed an additive antitumor effect. CONCLUSION: Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL.
Subject(s)
Biomarkers, Tumor/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Lymphoma, Mantle-Cell/metabolism , Molecular Targeted Therapy , Protein Interaction Domains and Motifs/drug effects , Transcription Factors/antagonists & inhibitors , Apoptosis , Cell Proliferation , Humans , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Tumor Cells, CulturedABSTRACT
A 47-year-old male was admitted to our hospital because of left hypochondrium part pain and was diagnosed with splenomegaly with splenic infarctions in May 2016. His complete blood cell count was almost within normal limits, and a bone marrow biopsy revealed normal cellularity with no fibrosis. In addition, no abnormal uptake was noted on FDG PET/CT. In August 2016, he underwent splenectomy for splenomegaly. The histological examination revealed fibrotic stenosis of the blood vessels in the spleen. After splenectomy, his platelet count elevated and remained at >1,000×109/l 3 months later. Finally, he was diagnosed with latent essential thrombocythemia (ET) because the JAK2V617F mutation was positive. Accordingly, oral hydroxyurea was initiated. Thrombosis could be a complication in myeloproliferative neoplasms (MPN). In our case, ET was masked, perhaps, because of hypersplenism and splenomegaly because of splenic vein thrombosis. Hence, examination of the JAK2V617F mutation in patients with splanchnic vein thrombosis is recommended because of the possibility of latent MPN.
Subject(s)
Splenectomy , Splenomegaly/surgery , Thrombocythemia, Essential/diagnosis , Humans , Janus Kinase 2/genetics , Male , Middle Aged , Mutation , Positron Emission Tomography Computed TomographyABSTRACT
A 61-year-old female was diagnosed with a lymphoid crisis of chronic myeloid leukemia (CML) in February 201X and started chemotherapy combined with dasatinib (DAS). After 1 month of initiating second consolidation therapy, the neutrophils decreased to 1%, bone marrow examination revealed large granular lymphocytes (LGL) at 13%, and complete cytogenetic remission was attained (CCyR). Suspecting DAS-induced agranulocytosis, DAS was discontinued. After 2 weeks, LGL disappeared and neutrophils recovered. In this case, CCyR was attained for the first time when LGL increased. We considered that the expansion of LGL correlated with the clinical efficacy, and agranulocytosis was an off-target effect of DAS.
