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1.
J Biol Chem ; 296: 100285, 2021.
Article in English | MEDLINE | ID: mdl-33450231

ABSTRACT

DNA methylation regulates gene transcription and is involved in various physiological processes in mammals, including development and hematopoiesis. It is catalyzed by DNA methyltransferases including Dnmt1, Dnmt3a, and Dnmt3b. For Dnmt3b, its effects on transcription can result from its own DNA methylase activity, the recruitment of other Dnmts to mediate methylation, or transcription repression in a methylation-independent manner. Low-frequency mutations in human DNMT3B are found in hematologic malignancies including cutaneous T-cell lymphomas, hairy cell leukemia, and diffuse large B-cell lymphomas. Moreover, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. However, it is poorly understood how the different Dnmt3b activities contribute to these outcomes. We modulated Dnmt3b activity in vivo by generating Dnmt3b+/- mice expressing one wild-type allele as well as Dnmt3b+/CI and Dnmt3bCI/CI mice where one or both alleles express catalytically inactive Dnmt3bCI. We show that 43% of Dnmt3b+/- mice developed T-cell lymphomas, chronic lymphocytic leukemia, and myeloproliferation over 18 months, thus resembling phenotypes previously observed in Dnmt3a+/- mice, possibly through regulation of shared target genes. Interestingly, Dnmt3b+/CI and Dnmt3bCI/CI mice survived postnatal development and were affected by B-cell rather than T-cell malignancies with decreased penetrance. Genome-wide hypomethylation, increased expression of oncogenes such as Jdp2, STAT1, and Trip13, and p53 downregulation were major events contributing to Dnmt3b+/- lymphoma development. We conclude that Dnmt3b catalytic activity is critical to prevent B-cell transformation in vivo, whereas accessory and methylation-independent repressive functions are important to prevent T-cell transformation.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoma, B-Cell/genetics , Lymphoma, T-Cell/genetics , Myeloproliferative Disorders/genetics , Neoplasms, Experimental/genetics , ATPases Associated with Diverse Cellular Activities/genetics , ATPases Associated with Diverse Cellular Activities/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , DNA (Cytosine-5-)-Methyltransferases/deficiency , DNA Methylation , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Female , Gene Expression Regulation, Neoplastic , Heterozygote , Homozygote , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphoma, B-Cell/enzymology , Lymphoma, B-Cell/pathology , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , Male , Mice , Mice, Knockout , Myeloproliferative Disorders/enzymology , Myeloproliferative Disorders/pathology , Neoplasms, Experimental/enzymology , Neoplasms, Experimental/pathology , Repressor Proteins/genetics , Repressor Proteins/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , DNA Methyltransferase 3B
2.
Molecules ; 25(9)2020 May 11.
Article in English | MEDLINE | ID: mdl-32403277

ABSTRACT

Multidrug resistance (MDR) is a severe problem in the treatment of cancer with overexpression of glycoprotein P (Pgp, ABCB1) as a reason for chemotherapy failure. A series of 14 novel 5-arylideneimidazolone derivatives containing the morpholine moiety, with respect to two different topologies (groups A and B), were designed and obtained in a three- or four-step synthesis, involving the Dimroth rearrangement. The new compounds were tested for their inhibition of the ABCB1 efflux pump in both sensitive (parental (PAR)) and ABCB1-overexpressing (MDR) T-lymphoma cancer cells in a rhodamine 123 accumulation assay. Their cytotoxic and antiproliferative effects were investigated by a thiazolyl blue tetrazolium bromide (MTT) assay. For active compounds, an insight into the mechanisms of action using either the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp was performed. The safety profile in vitro was examined. Structure-activity relationship (SAR) analysis was discussed. The most active compounds, representing both 2-substituted- (11) and Dimroth-rearranged 3-substituted (18) imidazolone topologies, displayed 1.38-1.46 fold stronger efflux pump inhibiting effects than reference verapamil and were significantly safer than doxorubicin in cell-based toxicity assays in the HEK-293 cell line. Results of mechanistic studies indicate that active imidazolones are substrates with increasing Pgp ATPase activity, and their dye-efflux inhibition via competitive action on the Pgp verapamil binding site was predicted in silico.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Imidazoles/chemistry , Imidazoles/pharmacology , Lymphoma, T-Cell/metabolism , ATP Binding Cassette Transporter, Subfamily B/chemistry , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/pharmacology , Drug Resistance, Multiple/genetics , Humans , Imidazoles/chemical synthesis , In Vitro Techniques , Inhibitory Concentration 50 , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/genetics , Mice , Models, Molecular , Molecular Docking Simulation , Morpholines/chemistry , Rhodamine 123/metabolism , Structure-Activity Relationship , Verapamil/pharmacology
3.
Blood Adv ; 3(11): 1778-1787, 2019 06 11.
Article in English | MEDLINE | ID: mdl-31186254

ABSTRACT

High-risk lymphomas (HRLs) are associated with dismal outcomes and remain a therapeutic challenge. Recurrent genetic and molecular alterations, including c-myc expression and aurora A kinase (AAK) and polo-like kinase-1 (PLK1) activation, promote cell proliferation and contribute to the highly aggressive natural history associated with these lymphoproliferative disorders. In addition to its canonical targets regulating mitosis, the AAK/PLK1 axis directly regulates noncanonical targets, including c-myc. Recent studies demonstrate that HRLs, including T-cell lymphomas and many highly aggressive B-cell lymphomas, are dependent upon the AAK/PLK1 axis. Therefore, the AAK/PLK1 axis has emerged as an attractive therapeutic target in these lymphomas. In addition to reviewing these recent findings, we summarize the rationale for targeting AAK/PLK1 in high-risk and c-myc-driven lymphoproliferative disorders.


Subject(s)
Aurora Kinase A/metabolism , Cell Cycle Proteins/metabolism , Lymphoma, B-Cell/enzymology , Lymphoma, T-Cell/enzymology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction , Animals , Humans , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/therapy , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/therapy , Proto-Oncogene Proteins c-myc/metabolism , Risk Factors , Polo-Like Kinase 1
4.
Int J Med Sci ; 16(3): 424-442, 2019.
Article in English | MEDLINE | ID: mdl-30911277

ABSTRACT

T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.


Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Lymphoma, T-Cell/drug therapy , Molecular Targeted Therapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Autophagy/physiology , Cytokines/metabolism , Depsipeptides/administration & dosage , Depsipeptides/pharmacology , Epigenesis, Genetic , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Histone Deacetylases/genetics , Humans , Hydroxamic Acids/administration & dosage , Lymphoma, T-Cell/enzymology , Sulfonamides/administration & dosage , Vorinostat/pharmacology
5.
Nat Med ; 25(1): 130-140, 2019 01.
Article in English | MEDLINE | ID: mdl-30510251

ABSTRACT

In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-ß. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.


Subject(s)
Lymphoma, T-Cell/metabolism , Tumor Suppressor Proteins/metabolism , Wiskott-Aldrich Syndrome Protein/metabolism , Anaplastic Lymphoma Kinase/metabolism , Animals , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Survival , Cytoskeletal Proteins/metabolism , Down-Regulation , Enzyme Activation , Extracellular Signal-Regulated MAP Kinases/metabolism , Guanosine Triphosphate/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Kaplan-Meier Estimate , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , MAP Kinase Signaling System , Mice , Protein Binding , STAT3 Transcription Factor/metabolism , T-Lymphocytes/immunology , Wiskott-Aldrich Syndrome Protein/deficiency , cdc42 GTP-Binding Protein/metabolism
6.
Vet Pathol ; 55(1): 98-107, 2018 01.
Article in English | MEDLINE | ID: mdl-29254476

ABSTRACT

Molecular clonality analysis of T-cell receptor (TCR) genes for diagnosing T-cell lymphoma is widely used in veterinary medicine. However, differentiating chronic enteritis (CE) from intestinal lymphoma is challenging because of the incompatibility between histopathologic and clonality analysis results. On the basis of findings that canine intestinal T-cell lymphoma and celiac disease share some common features, we conducted serologic examinations in combination with histopathologic and T-cell receptor clonality analyses in 48 dogs diagnosed with either CE or intestinal lymphoma. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies against gliadin and tissue transglutaminase (tTG) were quantitatively measured using ELISA. The conditions were classified according to the histopathologic diagnosis, clonality analysis, and combined histopathologic/clonality analysis. Histopathologic analysis showed that dogs with intestinal lymphoma were likely to have high levels of serum IgA antibodies against gliadin and tTG, and serum IgG antibodies against tTG. No correlation between the diagnosed groups and control group was observed in the results of the clonality analysis and histopathologic/clonality analysis. It is interesting that dogs with intestinal lymphoma had a higher serum IgA titer against gliadin and tTG than did dogs with CE. These results suggest an association between repetitive inflammatory stimulation by gliadin peptides and subsequent intestinal lymphoma in dogs.


Subject(s)
Dog Diseases/immunology , Enteritis/veterinary , GTP-Binding Proteins/immunology , Gliadin/immunology , Immunoglobulin A/immunology , Intestinal Neoplasms/veterinary , Lymphoma, T-Cell/veterinary , Transglutaminases/immunology , Animals , Blotting, Western/veterinary , Chronic Disease/veterinary , Diagnosis, Differential , Dog Diseases/diagnosis , Dog Diseases/enzymology , Dog Diseases/pathology , Dogs , Enteritis/enzymology , Enteritis/immunology , Enteritis/pathology , Enzyme-Linked Immunosorbent Assay/veterinary , Female , Immunoglobulin G/immunology , Intestinal Neoplasms/enzymology , Intestinal Neoplasms/immunology , Intestinal Neoplasms/pathology , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/immunology , Male , Microscopy, Fluorescence/veterinary , Polymerase Chain Reaction/veterinary , Protein Glutamine gamma Glutamyltransferase 2
7.
Mol Oncol ; 11(9): 1143-1155, 2017 09.
Article in English | MEDLINE | ID: mdl-28544264

ABSTRACT

The AMP-activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK ß1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK ß1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK ß1 accelerates the appearance of a T-cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin-1ß (IL1ß), reductions in acetyl-CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK ß1 subunit accelerate the development of T-cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53-mutant tumors.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Disease Progression , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , Tumor Suppressor Protein p53/deficiency , AMP-Activated Protein Kinases/deficiency , Acetyl-CoA Carboxylase , Animals , Gene Deletion , Lipogenesis , Mice, Inbred C57BL , Phosphorylation , Survival Analysis , Tumor Suppressor Protein p53/metabolism
8.
Cancer Sci ; 107(11): 1543-1549, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27554046

ABSTRACT

Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.


Subject(s)
Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/enzymology , Histone Deacetylase Inhibitors/pharmacology , Animals , Calcineurin/metabolism , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/enzymology , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/enzymology , Multiple Myeloma/drug therapy , Multiple Myeloma/enzymology
9.
Am J Surg Pathol ; 40(3): 335-41, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26574844

ABSTRACT

Angioimmunoblastic T-cell lymphoma (AITL) is a nodal-based mature T-cell lymphoma with distinctive clinical symptomatology and histology. Research into its pathogenesis supports a cellular derivation from follicular helper T cells and overexpression of genes related to B cells, follicular dendritic cells, and vascular growth. Recently, a novel recurring somatic mutation in RHOA, encoding p.Gly17Val, was discovered in nearly 70% of AITLs and in a smaller proportion of peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS). We investigated a series of AITLs to compare RHOA mutated with wild-type case for clinicopathologic differences. Targeted exome and Sanger sequencing was performed on 27 AITLs and 10 PTCL-NOS. The RHOA G17V mutation was identified in 63% of the AITL cases and in none of the PTCL-NOS cases. The median variant allelic frequency was 14%, with a range of 0.4 to 50% in positive cases. RHOA G17V-mutated cases had a significantly higher incidence of splenomegaly and B symptoms at diagnosis, but there was no difference in overall survival between mutated and wild-type subgroups. Cases with the RHOA G17V mutation had a significantly higher mean microvessel density (P<0.01) and expressed a greater number of follicular helper T-cell markers (P<0.05) than wild-type cases. RHOA G17V is present in a significant proportion of angioimmunoblastic lymphomas and is associated with classic pathologic features of AITL. Additional studies are needed to provide a biological or functional link between altered RHOA function and these pathologic features.


Subject(s)
Biomarkers, Tumor/genetics , Immunoblastic Lymphadenopathy/genetics , Lymphoma, T-Cell/genetics , Mutation , rhoA GTP-Binding Protein/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , DNA Mutational Analysis , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Immunoblastic Lymphadenopathy/enzymology , Immunoblastic Lymphadenopathy/pathology , Immunohistochemistry , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , Male , Microvessels/pathology , Middle Aged , Phenotype , Splenomegaly/genetics , Splenomegaly/pathology
10.
Hum Mol Genet ; 24(22): 6331-49, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26310626

ABSTRACT

Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model. These mice recapitulate many of the characteristics of A-T seen in humans, with the notable exception of neurodegeneration. In order to study how an N-terminal mutation affects the disease phenotype, we generated an inducible Atm mutant mouse model (Atm(tm1Mmpl/tm1Mmpl), referred to as A-T [M]) predicted to express only the first 62 amino acids of Atm. Cells derived from A-T [M] mutant mice exhibited reduced cellular proliferation and an altered DNA damage response, but surprisingly, showed no evidence of an oxidative imbalance. Examination of the A-T [M] animals revealed an altered immunophenotype consistent with A-T. In contrast to mice harboring C-terminal Atm mutations that disproportionately develop thymic lymphomas, A-T [M] mice developed lymphoma at a similar rate as human A-T patients. Morphological analyses of A-T [M] cerebella revealed no substantial cellular defects, similar to other models of A-T, although mice display behavioral defects consistent with cerebellar dysfunction. Overall, these results suggest that loss of Atm is not necessarily associated with an oxidized phenotype as has been previously proposed and that loss of ATM protein is not sufficient to induce cerebellar degeneration in mice.


Subject(s)
Ataxia Telangiectasia/genetics , Lymphoma, T-Cell/genetics , Mutation , Animals , Ataxia Telangiectasia/enzymology , Ataxia Telangiectasia/metabolism , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Behavior, Animal/physiology , Cell Cycle Proteins/genetics , DNA Damage , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Genetic Association Studies , Humans , Incidence , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/metabolism , Male , Mice , Mice, Inbred C57BL , Oxidation-Reduction , Tumor Suppressor Proteins/genetics
11.
Ann Diagn Pathol ; 19(3): 113-6, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25787243

ABSTRACT

BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders.


Subject(s)
Dendritic Cell Sarcoma, Interdigitating/enzymology , Proto-Oncogene Proteins B-raf/metabolism , B-Lymphocytes/enzymology , B-Lymphocytes/pathology , Cell Transdifferentiation/physiology , Dendritic Cell Sarcoma, Interdigitating/genetics , Dendritic Cell Sarcoma, Interdigitating/pathology , Female , Flow Cytometry , Histiocytosis, Langerhans-Cell/enzymology , Histiocytosis, Langerhans-Cell/genetics , Histiocytosis, Langerhans-Cell/pathology , Humans , Immunohistochemistry , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , Male , Middle Aged , Mutation , Polymerase Chain Reaction
12.
Cancer Lett ; 357(1): 265-278, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25444924

ABSTRACT

Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro-oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from plumbagin-induced apoptosis. Further, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Dual Specificity Phosphatase 1/antagonists & inhibitors , Dual-Specificity Phosphatases/antagonists & inhibitors , Glutathione/metabolism , Lymphoma, T-Cell/drug therapy , Mitogen-Activated Protein Kinase Phosphatases/antagonists & inhibitors , Naphthoquinones/pharmacology , Oxidative Stress/drug effects , Animals , Apoptosis/drug effects , Disease Models, Animal , Dual Specificity Phosphatase 1/metabolism , Dual-Specificity Phosphatases/metabolism , Enzyme Activation , Humans , Jurkat Cells , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/metabolism , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Models, Molecular , Phosphorylation , Random Allocation
13.
Blood ; 125(5): 852-5, 2015 Jan 29.
Article in English | MEDLINE | ID: mdl-25477498

ABSTRACT

Mice with T-cell-specific loss of the tumor suppressor gene PTEN early in T-cell ontogeny develop thymic lymphomas that invariably harbor a reciprocal translocation involving the T-cell receptor α/δ locus and c-myc, t(14;15). In addition to its known function as a lipid phosphatase opposing PI3K signaling, PTEN has also been described as playing a prominent role in promoting genomic stability. As a result, it has been uncertain which one(s) of these 2 separable features were required to block the development of lymphoma. Here, using a conditional model in which T cells selectively express 1 phosphatase-dead PTEN mutant (C124S) and maintain 1 null allele, we show that PTEN phosphatase activity is required for preventing the emergence of a malignant T-cell population harboring t(14;15), thus constituting a critical function of PTEN in preventing lymphomagenesis.


Subject(s)
Gene Expression Regulation, Neoplastic , Lymphoma, T-Cell/genetics , PTEN Phosphohydrolase/genetics , T-Lymphocytes/enzymology , Thymus Neoplasms/genetics , Animals , Bone Marrow/enzymology , Bone Marrow/pathology , Chimera/genetics , Chimera/metabolism , Chromosomes, Mammalian , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/pathology , Mice , Mice, Knockout , PTEN Phosphohydrolase/deficiency , Protein Isoforms/deficiency , Protein Isoforms/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Signal Transduction , T-Lymphocytes/pathology , Thymus Gland/enzymology , Thymus Gland/pathology , Thymus Neoplasms/enzymology , Thymus Neoplasms/pathology , Translocation, Genetic
14.
Int J Clin Exp Pathol ; 7(9): 6097-107, 2014.
Article in English | MEDLINE | ID: mdl-25337257

ABSTRACT

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma (PTCL) of follicular helper T-cell origin and is rare in Taiwan. There are overlapping features of AITL and peripheral T-cell lymphoma with a follicular growth pattern (PTCL-F). Around one fifth of PTCL-F exhibits t(5;9)(q33;q22)/ITK-SYK chromosomal translocation, which is essentially absent in AITL. We retrospectively investigated 35 cases of AITL from Taiwan with histopathology review, immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBV) and fluorescence in situ hybridization (FISH) for t(5;9)(q33;q22)/ITK-SYK and correlated the results with overall survival. Twenty-six cases of not otherwise specified PTCL (PTCL-NOS) were also examined by FISH for comparison. Most AITL patients were male (69%) and elderly (median age at 67 years) with frequent bone marrow involvement (53%), high Ann Arbor stages (77%), and elevated serum lactate dehydrogenase (68%). Most cases (80%) showed a typical CD4+/CD8- phenotype and in 90% cases there were scattered EBV-positive B-cells (less than 10% cells). None of these cases showed t(5;9)(q33;q22)/ITK-SYK translocation by FISH. Gain of ITK and SYK gene was identified in 38% and 14% tumors, respectively, but both were not associated with overall survival. Performance status < 2 was associated with a better outcome but not the other clinicopathological factors. All PTCL-NOS cases were negative for ITK-SYK translocation with similar rates (38% and 12%, respectively) of gains at ITK and SYK loci as that of AITL. In this so far the largest series of AITL from Taiwan, we reported the clinicopathological features and FISH findings on ITK and SYK genes. We confirmed the absence of t(5;9)(q33;q22)/ITK-SYK translocation, which may serve as an additional differential diagnostic tool from PTCL-F when present. PTCL-NOS shared a similar pattern of ITK and SYK gains with AITL. More studies are warranted to elucidate the roles of SYK and ITK and other genes in the lymphomagenesis of AITL in Taiwan.


Subject(s)
Gene Amplification/genetics , Immunoblastic Lymphadenopathy/genetics , Lymphoma, T-Cell/genetics , Protein-Tyrosine Kinases/genetics , Aged , Aged, 80 and over , Asian People/genetics , Chromosomes, Human, Pair 5 , Chromosomes, Human, Pair 9 , Female , Genetic Predisposition to Disease , Herpesvirus 4, Human/isolation & purification , Humans , Immunoblastic Lymphadenopathy/enzymology , Immunoblastic Lymphadenopathy/ethnology , Immunoblastic Lymphadenopathy/pathology , Immunoblastic Lymphadenopathy/virology , Immunohistochemistry , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins/genetics , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/ethnology , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/virology , Male , Middle Aged , Phenotype , Predictive Value of Tests , Prognosis , Retrospective Studies , Syk Kinase , Taiwan/epidemiology , Time Factors , Translocation, Genetic
15.
Mol Biol Rep ; 41(7): 4187-97, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24574001

ABSTRACT

Antioxidants protect the cells from the damaging effects of reactive oxygen species (ROS). Production of ROS during cellular metabolism is balanced by their removal by antioxidants. Any condition leading to increased levels of ROS results in oxidative stress, which participates in multistage carcinogenesis by causing oxidative DNA damage, mutations in the proto-oncogenes and tumor suppressor genes. Antioxidant defense system is required to overcome the process of carcinogenesis generated by ROS. Antioxidant enzymes are major contributors to endogenous antioxidant defense system. Protein kinase C (PKC) is generally involved in cell proliferation and its over expression leads to abnormal tumor growth. Out of three classes of PKC, classical PKC is mainly involved in cell proliferation and tumor growth. Classical PKC initiates signaling pathway and leads to activation of a number of downstream protein via activation of NF-κB. Therefore any agent which can promotes the endogenous antioxidant defense system should be able to down regulate PKC and NF-κB activation and thus may be useful in reducing cancer progression. To investigate this hypothesis we have tested the effect of antioxidant ellagic acid on antioxidant enzymes and PKC signaling in Dalton's lymphoma bearing (DL) mice. DL mice were treated with three different doses of ellagic acid. The treatment significantly increases the activity and expression of antioxidant enzymes and down regulates the expression of classical isozymes of PKC as well as the activation of NF-κB, indicating that ellagic acid improves antioxidant defense system and PKC signaling via NF-κB which may contribute to its cancer preventive role.


Subject(s)
Antioxidants/pharmacology , Ellagic Acid/pharmacology , Gene Expression Regulation, Neoplastic , Lymphoma, T-Cell/drug therapy , NF-kappa B/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Catalase/metabolism , Enzyme Activation/drug effects , Female , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/metabolism , Lymphoma, T-Cell/enzymology , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/pathology , Male , Mice , Mice, Inbred AKR , NF-kappa B/genetics , NF-kappa B/metabolism , Oxidative Stress/drug effects , Protein Kinase C/genetics , Protein Kinase C/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal Transduction , Superoxide Dismutase/metabolism
16.
J Clin Oncol ; 32(1): 44-50, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24043741

ABSTRACT

PURPOSE: Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. PATIENTS AND METHODS: Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. RESULTS: We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. CONCLUSION: The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.


Subject(s)
Antineoplastic Agents/therapeutic use , Aurora Kinase A/antagonists & inhibitors , Azepines/therapeutic use , Burkitt Lymphoma/drug therapy , Lymphoma, Follicular/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, T-Cell/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Azepines/administration & dosage , Azepines/adverse effects , Azepines/pharmacokinetics , Burkitt Lymphoma/enzymology , Drug Administration Schedule , Female , Humans , Lymphoma, Follicular/enzymology , Lymphoma, Large B-Cell, Diffuse/enzymology , Lymphoma, Mantle-Cell/enzymology , Lymphoma, T-Cell/enzymology , Male , Middle Aged , Molecular Targeted Therapy/methods , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Recurrence , Treatment Outcome
17.
J Immunol ; 191(12): 6200-7, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24218456

ABSTRACT

Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4(+) T lymphocytes, at least in part, by using the pre-existing, IL-2-dependent signaling pathways.


Subject(s)
CD4-Positive T-Lymphocytes/pathology , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Interleukin-2/physiology , Lymphoma, T-Cell/enzymology , Oncogene Proteins, Fusion/physiology , Protein-Tyrosine Kinases/physiology , CD4-Positive T-Lymphocytes/enzymology , CD4-Positive T-Lymphocytes/metabolism , Carbazoles/pharmacology , Cell Line, Tumor , Early Growth Response Protein 1/biosynthesis , Early Growth Response Protein 1/genetics , Enzyme Activation , Humans , Lymphoma, T-Cell/genetics , MAP Kinase Signaling System , Molecular Mimicry , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Oncogene Proteins, Fusion/antagonists & inhibitors , Phenylurea Compounds/pharmacology , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Processing, Post-Translational , Protein-Tyrosine Kinases/antagonists & inhibitors , STAT3 Transcription Factor/physiology , STAT5 Transcription Factor/physiology , Signal Transduction/genetics
19.
PLoS One ; 8(6): e64536, 2013.
Article in English | MEDLINE | ID: mdl-23825522

ABSTRACT

Angioimmunoblastic T-cell Lymphoma (AITL) is one of the most frequent T-cell lymphoma entities. Follicular helper T lymphocytes (TFH) are recognized as the normal cellular counterpart of the neoplastic component. Despite a clonal T-cell feature and few described recurrent cytogenetic abnormalities, a driving oncogenic event has not been identified so far. It has been recently reported that in mice, heterozygous inactivation of Roquin/Rc3h1, a RING type E3 ubiquitine ligase, recapitulates many of the clinical, histological, and cellular features associated with human AITL. In this study we explored whether ROQUIN alterations could be an initial event in the human AITL oncogenic process. Using microarray and RT-PCR analyses, we investigated the levels of ROQUIN transcripts in TFH tumor cells purified from AITL (n = 8) and reactive tonsils (n = 12) and found similar levels of ROQUIN expression in both. Moreover, we also demonstrated that ROQUIN protein was expressed by AITL TFH (PD1+) cells. We then analysed ROQUIN coding sequence in 12 tumor cell-rich AITL samples and found no mutation in any of the samples. Finally, we analysed the expression of MiR101, a putative partner of ROQUIN involved in the modulation of ICOS expression and found similar levels of expression in tumor and reactive TFH. Altogether, this study shows that neither alteration of ROQUIN gene nor deregulation of miR101 expression is likely to be a frequent recurrent event in AITL.


Subject(s)
Immunoblastic Lymphadenopathy/enzymology , Lymphoma, T-Cell/enzymology , Ubiquitin-Protein Ligases/metabolism , Cells, Cultured , Humans , Immunoblastic Lymphadenopathy/genetics , Immunoblastic Lymphadenopathy/metabolism , Immunohistochemistry , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ubiquitin-Protein Ligases/genetics
20.
PLoS One ; 8(6): e65308, 2013.
Article in English | MEDLINE | ID: mdl-23762338

ABSTRACT

13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, induces apoptosis in human cancer cells. We investigated the inhibitory effects and mechanism of action of 13-MTD on T-cell non-Hodgkin's lymphoma (T-NHL) cell lines both in vitro and in vivo. Growth inhibition in response to 13-MTD was evaluated by the cell counting kit-8 (CCK-8) assay in three T-NHL cell lines (Jurkat, Hut78, EL4 cells). Flow cytometry analyses were used to monitor the cell cycle and apoptosis. Proteins involved in 13-MTD-induced apoptosis were examined in Jurkat cells by western blotting. We found that 13-MTD inhibited proliferation and induced the apoptosis of T-NHL cell lines. 13-MTD treatment also induced a concentration-dependent arrest of Jurkat cells in the G1-phase. During 13-MTD-induced apoptosis in Jurkat cells, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP, a caspase enzymolysis product) were detected after incubation for 2 h, and increased after extending the incubation time. However, there was no change in the expression of Bcl-2 or c-myc proteins. The appearance of apoptotic Jurkat cells was accompanied by the inhibition of AKT and nuclear factor-kappa B (NF-κB) phosphorylation. In addition, 13-MTD could also effectively inhibit the growth of T-NHL tumors in vivo in a xenograft model. The tumor inhibition rate in the experimental group was 40%. These data indicate that 13-MTD inhibits proliferation and induces apoptosis through the down-regulation of AKT phosphorylation followed by caspase activation, which may provide a new approach for treating T-cell lymphomas.


Subject(s)
Caspase 3/metabolism , Down-Regulation/drug effects , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/enzymology , Myristic Acids/pharmacology , Myristic Acids/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Lymphoma, T-Cell/pathology , Mice , Mice, Nude , Myristic Acids/administration & dosage , NF-kappa B/metabolism , Neoplasm Proteins/metabolism , Phosphorylation/drug effects , Poly(ADP-ribose) Polymerases/metabolism , Xenograft Model Antitumor Assays
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