cyclin-d1 and Lymphoma--T-Cell

Secondary cutaneous involvement by mantle cell lymphoma (MCL), an uncommon aggressive B-cell malignancy, predominantly involves the dermis, with few reports of pannicular involvement. Lymphocytic infiltration of subcutaneous tissue is associated with inflammatory panniculitides and certain T-cell lymphomas, primarily subcutaneous panniculitis-like T-Cell lymphoma (SPTCL), which is characterized by rimming of adipocytes by tumor cells. We report the case of a 69-year-old man with a history of systemic nodal MCL who presented with subcutaneous nodules on his lower extremities after receiving multi-agent chemotherapy. Biopsies showed a dense infiltrate of atypical, mitotically active, monomorphic, medium-sized lymphoid cells in the subcutaneous fat with prominent rimming of the adipocytes by the tumor cells. These features were not morphologically typical of MCL. Immunohistochemistry showed these cells to be CD20+, CD5+ B-cells with strong cyclin D1 expression; fluorescence in situ hybridization (FISH) analysis was positive for t(11;14)(q13;32), confirming the diagnosis of secondary cutaneous involvement of MCL. This represents an exceptional report of cutaneous MCL presenting clinically and histologically with a panniculitis-type pattern and adipocyte rimming, histomorphologically mimicking SPTCL. Noteworthy examples, such as this report, support the practice of utilizing clinical correlation, immunohistochemistry, and/or molecular cytogenetics to confirm the diagnosis of any case suspicious for cutaneous lymphoma.

Topics: Aged; Antigens, CD20; B-Lymphocytes; CD5 Antigens; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Diagnosis, Differential; Humans; Lymphoma, Mantle-Cell; Lymphoma, T-Cell; Male; Panniculitis; Skin Neoplasms; Translocation, Genetic

Adult T cell lymphoma is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-373 in T cell lymphoma.. We analyzed the levels of CCND1 and miR-373 in T cell lymphoma tissue and the relationship of miR-373 levels with patients' prognosis. We then overexpressed miR-373 by miRNA mimics transfection and inhibited miR-373 by miRNA antisense transfection in T cell lymphoma cells. Cell survival and growth were analyzed by CCK-8 assay and MTT assay, respectively. Cell proliferation was analyzed by flow cytometry. Bioinformatics analyses were applied to predict miR-373 targets, which were then confirmed by luciferase reporter assay.. We detected significantly higher levels of CCND1, and significantly lower levels of miR-373 in T cell lymphoma tissue, compared to the adjacent non-tumor tissue. Moreover, the low miR-373 levels were associated with poor survival of the patients. Overexpression of miR-373 significantly inhibited cell growth, while depletion of miR-373 increased cell growth in T cell lymphoma cells. Moreover, the effects of miR-373 on cell growth appeared to result from an alteration in cell proliferation. Finally, miR-373 was found to bind to the 3'-UTR of CCND1 mRNA to inhibit its translation in T cell lymphoma cells.. Our study suggests that reduced miR-373 levels in T cell lymphoma tissue may promote T cell lymphoma growth, possibly through CCND1-mediated cell proliferation.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Gene Expression Regulation, Leukemic; Humans; Lymphoma, T-Cell; MicroRNAs

Protein arginine methyltransferase 5 (PRMT5) has been implicated as a key modulator of lymphomagenesis. Whether PRMT5 has overt oncogenic function in the context of leukemia/lymphoma and whether it represents a therapeutic target remains to be established. We demonstrate that inactivation of PRMT5 inhibits colony-forming activity by multiple oncogenic drivers, including cyclin D1, c-MYC, NOTCH1, and MLL-AF9. Furthermore, we demonstrate that PRMT5 overexpression specifically cooperates with cyclin D1 to drive lymphomagenesis in a mouse model, revealing inherent neoplastic activity. Molecular analysis of lymphomas revealed that arginine methylation of p53 selectively suppresses expression of crucial proapoptotic and antiproliferative target genes, thereby sustaining tumor cell self-renewal and proliferation and bypassing the need for the acquisition of inactivating p53 mutations. Critically, analysis of human tumor specimens reveals a strong correlation between cyclin D1 overexpression and p53 methylation, supporting the biomedical relevance of this pathway.. We have identified and functionally validated a crucial role for PRMT5 for the inhibition of p53-dependent tumor suppression in response to oncogenic insults. The requisite role for PRMT5 in the context of multiple lymphoma/leukemia oncogenic drivers suggests a molecular rationale for therapeutic development.

Topics: Adaptor Proteins, Signal Transducing; Amino Acid Substitution; Animals; Apoptosis; Arginine; Cell Transformation, Neoplastic; Cluster Analysis; Cyclin D1; Cyclin-Dependent Kinase 4; Enzyme Activation; Gene Expression Profiling; Humans; Leukemia, T-Cell; Lymphoma; Lymphoma, T-Cell; Methylation; Mice; Mutation; Oncogenes; Phosphorylation; Protein-Arginine N-Methyltransferases; Tumor Suppressor Protein p53

We have shown in vitro that thyroid hormones (THs) regulate the balance between proliferation and apoptosis of T lymphoma cells. The effects of THs on tumor development have been studied, but the results are still controversial. Herein, we show the modulatory action of thyroid status on the in vivo growth of T lymphoma cells. For this purpose, euthyroid, hypothyroid, and hyperthyroid mice received inoculations of EL4 cells to allow the development of solid tumors. Tumors in the hyperthyroid animals exhibited a higher growth rate, as evidenced by the early appearance of palpable solid tumors and the increased tumor volume. These results are consistent with the rate of cell division determined by staining tumor cells with carboxyfluorescein succinimidyl ester. Additionally, hyperthyroid mice exhibited reduced survival. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. Additionally, only tumors from hyperthyroid animals had increased expression levels of proliferating cell nuclear antigen and active caspase 3. Differential expression of cell cycle regulatory proteins was also observed. The levels of cyclins D1 and D3 were augmented in the tumors of the hyperthyroid animals, whereas the cell cycle inhibitors p16/INK4A (CDKN2A) and p27/Kip1 (CDKN1B) and the tumor suppressor p53 (TRP53) were increased in hypothyroid mice. Intratumoral and peritumoral vasculogenesis was increased only in hyperthyroid mice. Therefore, we propose that the thyroid status modulates the in vivo growth of EL4 T lymphoma through the regulation of cyclin, cyclin-dependent kinase inhibitor, and tumor suppressor gene expression, as well as the stimulation of angiogenesis.

Topics: Animals; Apoptosis; Caspase 3; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Female; Hyperthyroidism; Hypothyroidism; Lymphoma, T-Cell; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neovascularization, Pathologic; Proliferating Cell Nuclear Antigen; Thyroid Gland; Tumor Suppressor Protein p53

The role of enhancer of zeste homolog 2 (EZH2) in cancer is complex and may vary depending on the cellular context. We found that EZH2 is aberrantly overexpressed in the majority of natural killer/T-cell lymphoma (NKTL), an aggressive lymphoid malignancy with very poor prognosis. We show that EZH2 upregulation is mediated by MYC-induced repression of its regulatory micro RNAs and EZH2 exerts oncogenic properties in NKTL. Ectopic expression of EZH2 in both primary NK cells and NKTL cell lines leads to a significant growth advantage. Conversely, knock-down of EZH2 in NKTL cell lines results in cell growth inhibition. Intriguingly, ectopic EZH2 mutant deficient for histone methyltransferase activity is also able to confer growth advantage and rescue growth inhibition on endogenous EZH2 depletion in NKTL cells, indicating an oncogenic role of EZH2 independent of its gene-silencing activity. Mechanistically, we show that EZH2 directly promotes the transcription of cyclin D1 and this effect is independent of its enzymatic activity. Furthermore, depletion of EZH2 using a PRC2 inhibitor 3-deazaneplanocin A significantly inhibits growth of NK tumor cells. Therefore, our study uncovers an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL and suggests that targeting EZH2 may have therapeutic usefulness in this lymphoma.

Topics: Adenosine; Adolescent; Adult; Aged; Aged, 80 and over; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Enhancer of Zeste Homolog 2 Protein; Female; Gene Expression Regulation, Neoplastic; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Killer Cells, Natural; Lymphoma, T-Cell; Male; MicroRNAs; Middle Aged; Mutagenesis; Polycomb Repressive Complex 2; Promoter Regions, Genetic; Up-Regulation; Young Adult

Natural killer/T-cell lymphoma (NKTL) is a highly aggressive disease. Despite the use of various treatment regimens, the prognosis of NKTL is poor, and new treatment strategies need to be determined. Because of the significant survival potential, nuclear factor (NF)-kappaB has become one of the major targets for drug development. In this study, we explored the effect and action mechanism of NF-kappaB inhibitors, BAY 11-7082 and curcumin, on NKTL cell lines (NKL, NK-92 and HANK1). Electrophoretic mobility shift assay showed that NF-kappaB was constitutively active in HANK1, a chemoresistant cell line. BAY 11-7082 and curcumin suppressed NF-kappaB activation in a time- and dose-dependent manner, which finally resulted in cell death. BAY 11-7082- and curcumin-induced cell death was associated with downregulation of Bcl-xL, cyclin D1, XIAP and c-FLIP, followed by caspase-8, poly(ADP-ribose) polymerase cleavage and activation. Given that the chemoresistant NK-92 cells respond to NF-kappaB inhibitors but not to conventional drugs, BAY 11-7082 and curcumin could be potentially useful for achieving improved outcome in chemotherapy-refractory NKTL.

Topics: bcl-X Protein; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Caspases; Cell Line, Tumor; Curcumin; Cyclin D1; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Humans; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Lymphoma, T-Cell; NF-kappa B; Nitriles; Poly(ADP-ribose) Polymerases; Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfones; Time Factors; X-Linked Inhibitor of Apoptosis Protein

The present study aimed to characterize the clinical and molecular-cytogenetic features of non-Hodgkin's lymphoma (NHL) with double translocation of the immunoglobulin heavy chain (IGH) gene. G-banding analysis, fluorescence in situ hybridization (FISH) with the IGH (Cgamma and VH) and oncogene (c-MYC, BCL1, BCL2, and BCL6) probes, and long-distance polymerase chain reaction (LD-PCR) were performed on 6 patients with B-cell lymphoma, one with angioimmunoblastic T-cell lymphoma, and one with acute lymphoblastic leukemia (ALL) with B-cell phenotype. G-banding analysis detected two different 14q32 translocations, t(14,18) and add (14)(q32) in a patient with ALL. Two distinct partners of double IGH translocation identified by FISH were as follows: c-MYC + BCL2 in 3 patients, c-MYC + BCL1 in 2, c-MYC + BCL6 in one, BCL2 + 9q22 in one, and 1q21 + 6q27 in one. Colocalization of BCL1 and c-MYC probes was demonstrated in a patient with mantle cell lymphoma. LD-PCR detected c-MYC/Cmu, c-MYC/Calpha and BCL6/Cmu, and c-MYC/Calpha fusion in each one patient. Seven of 8 patients showed high serum LDH. Central nervous system and leukemic involvement was observed in 5 and 6 patients, respectively. Median survival time of patients with c-MYC/IGH translocation was 9 months. The results defined a clinical subset of B-cell lymphoma/leukemia showing extremely poor prognosis. C-MYC/IGH translocation is possibly an evolutionary alteration following the primary IGH translocation with BCL1, BCL2, or BCL6. Furthermore, FISH identified one novel (9q22) and one cryptic chromosomal breakpoints (6q27) involved in IGH translocation.

Topics: Adult; Aged; Chromosome Banding; Cyclin D1; Cytogenetic Analysis; DNA-Binding Proteins; Female; Genes, Immunoglobulin; Humans; Immunoglobulin Heavy Chains; In Situ Hybridization, Fluorescence; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Lymphoma, T-Cell; Male; Middle Aged; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; Transcription Factors; Translocation, Genetic

The contribution of oncogene amplification and/or overexpression to T-cell lymphoid neoplasms has only of late been established with the implication of the TCL1 and MTCP1 genes in T-cell malignancies. Our laboratory has recently discovered a novel oncogene, MCT-1, amplified in a T-cell lymphoma and mapped to chromosome Xq22-24. MCT-1 has been shown to decrease cell-doubling time, dramatically shortening the duration of G(1) transit time and/or G1-S transition, and transforms NIH3T3 fibroblasts. Constitutive expression of MCT-1 results in a strong proliferative signal and is associated with deregulation of protein kinase-mediated G1/S phase checkpoints. In this study we analysed the level and subcellular localization of this novel cell cycle regulatory molecule as a function of cell cycle phase. In human lymphoid tumors expression of MCT-1 is constant throughout the cell cycle and remains cytoplasmic. Cells overexpressing MCT-1 have increased expression of cyclin D1 with dysregulation of the G(1)-S checkpoint. Both cyclin D1 and MCT-1 are involved in regulating passage of cells through the G1 phase of the cell cycle. Since prior work has shown that gamma irradiation induces cyclin D1 expression we investigated the induction of MCT-1 to DNA damaging agents. We demonstrate that increases in MCT-1 protein in irradiated human lymphoid cells do not occur at the mRNA level and do not require new protein synthesis.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Cell Nucleus; Cyclin D1; Cytoplasm; DNA Damage; Doxorubicin; G1 Phase; Gene Expression Regulation, Neoplastic; Hot Temperature; Humans; Immunoblotting; Jurkat Cells; Lymphoma, T-Cell; Mice; Oncogene Proteins; Paclitaxel; RNA, Messenger; S Phase; Subcellular Fractions; Time Factors; X Chromosome

Topics: Aged; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Herpesvirus 4, Human; Humans; Immunohistochemistry; Killer Cells, Natural; Lymphoma, T-Cell; Nose Neoplasms; Retinoblastoma Protein; Tumor Suppressor Protein p53

Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the cyclin D1 gene and deficient expression of the retinoblastoma gene in 42 and 28% of these tumors, respectively. The immunohistochemical analysis showed that these RT-PCR results are correlated with a significant increase in the number of positive cells for cyclin D1 and a moderate decrease in the expression of Rb protein, respectively. The analysis of cyclin D1, Rb, p15(INK4b) and p16(INK4a) showed that 75% of lymphomas had alterations in these genes and indicates that the Rb pathway is frequently altered in mouse primary T cell lymphomas. Moreover, 31% of lymphomas presented simultaneous alterations in at least two of these genes, suggesting the importance of concurrent alteration of different Rb pathway regulators. In addition, we have characterized these samples for mutational status of the N-ras and K-ras genes. We have only detected mutations in codon 12 of K-ras in six of 49 lymphomas (12%). Interestingly, five of these lymphomas also showed alterations in at least one of the Rb pathway regulators analyzed here. Taken together, these data suggest that deregulation of the Rb pathway regulators and/or oncogenic activation of K-ras may represent a common important clue in progression of murine T cell lymphomas.

Topics: Animals; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Codon; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; DNA Mutational Analysis; Female; Gene Expression Regulation, Neoplastic; Genes, p16; Genes, ras; Genes, Retinoblastoma; Lymphoma, T-Cell; Male; Mice; Mice, Inbred C57BL; Neoplasm Proteins; Neoplasms, Radiation-Induced; Polymorphism, Restriction Fragment Length; Proto-Oncogene Proteins; Retinoblastoma Protein; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Proteins

The G1 cyclin, cyclin D1, has been implicated in the development of human and mouse tumors. Here we describe immunohistochemical analyses of cyclin D1 for a large panel of mouse B cell tumors. In addition, we characterize cyclin D1 expression in a series of cultured cell lines that represent transformed B cells at different stages of development. Immunohistochemical analysis showed that for low-grade lymphomas, cyclin D1 was expressed by 83% of centroblastic centrocytic (CBCC) and 14% of small lymphocytic lymphomas (SLL). For high-grade tumors, 28% of B lymphoblastic and 23% of centroblastic tumors expressed cyclin D1, while all immunoblastic lymphomas were negative. Studies of RNA and protein prepared from cultured B lineage tumors showed that cyclin D1 was expressed by all pre-B and most B cell tumors but not by cell lines representative of late B cell differentiation or by plasma cells. Expression of cyclin D1 in the lymphomas was not associated with alterations in the genomic structure of the Fis-1 (Bcl-1) common proviral integration site or cyclin D1 itself or with cell growth activity as assessed by expression of proliferating cell nuclear antigen (PCNA).

Topics: Animals; Carrier Proteins; Cell Differentiation; Cyclin D1; DNA; Factor For Inversion Stimulation Protein; Gene Expression; Genes, myc; Immunohistochemistry; Integration Host Factors; Lymphoma, B-Cell; Lymphoma, T-Cell; Mice; Nucleic Acid Hybridization; Proliferating Cell Nuclear Antigen; RNA, Messenger; Tumor Cells, Cultured