ABSTRACT
Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells. Thus, it is unclear whether or not impairment of MMR causes the MSI in ATL cells. HTLV-1 bZIP factor (HBZ) protein interacts with numerous host transcription factors and significantly contributes to disease pathogenesis and progression. Here we investigated the effect of HBZ on MMR in normal cells. The ectopic expression of HBZ in MMR-proficient cells induced MSI, and also suppressed the expression of several MMR factors. We then hypothesized that the HBZ compromises MMR by interfering with a transcription factor, nuclear respiratory factor 1 (NRF-1), and identified the consensus NRF-1 binding site at the promoter of the gene encoding MutS homologue 2 (MSH2), an essential MMR factor. The luciferase reporter assay revealed that NRF-1 overexpression enhanced MSH2 promoter activity, while co-expression of HBZ reversed this enhancement. These results supported the idea that HBZ suppresses the transcription of MSH2 by inhibiting NRF-1. Our data demonstrate that HBZ causes impaired MMR, and may imply a novel oncogenesis driven by HTLV-1.
Subject(s)
Human T-lymphotropic virus 1 , Leukemia-Lymphoma, Adult T-Cell , Adult , Humans , Human T-lymphotropic virus 1/genetics , DNA Mismatch Repair , Retroviridae Proteins/genetics , Retroviridae Proteins/metabolism , MutS Homolog 2 Protein/genetics , MutS Homolog 2 Protein/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathologyABSTRACT
The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death and is a suitable therapeutic target for B-cell lymphomas.
Subject(s)
Apoptosis/genetics , B-Lymphocytes/enzymology , Cell Transformation, Neoplastic/genetics , Lymphoma, Large B-Cell, Diffuse/etiology , Multiprotein Complexes/physiology , Ubiquitin-Protein Ligases/genetics , Animals , B-Lymphocytes/pathology , Carrier Proteins/physiology , DNA Damage , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Intracellular Signaling Peptides and Proteins/physiology , Lymphoma, Large B-Cell, Diffuse/enzymology , Lymphoma, Large B-Cell, Diffuse/genetics , Mice , Mice, Transgenic , Mutation, Missense , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/physiology , NF-kappa B/metabolism , Neoplasm Transplantation , Polymorphism, Single Nucleotide , Polyubiquitin/biosynthesis , Protein Processing, Post-Translational , Transcription Factors/physiology , Transcriptome , Ubiquitin-Protein Ligases/analysis , Ubiquitin-Protein Ligases/physiology , Ubiquitination , Ubiquitins/physiologyABSTRACT
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading across the world. We encountered two patients with COVID-19 who underwent treatment for acute leukemia at initial diagnosis. Both the patients received conventional induction therapy without the exacerbation of COVID-19. Although the impact of SARS-CoV-2 on the treatment of leukemia is unclear, our treatment experience suggests that there is no major contraindication to standard chemotherapy for acute leukemia in patients with COVID-19. As COVID-19 continues to be a threat worldwide, further evaluations of large cohorts are needed for future treatment decisions for acute leukemia with COVID-19.
Subject(s)
COVID-19 , Leukemia , Humans , Polymerase Chain Reaction , SARS-CoV-2ABSTRACT
Adult T-cell leukemia (ATL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated-genome analysis has revealed mutations in many genes involved in the T-cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL-cell proliferation. We screened a siRNA library to examine signaling-pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell proliferation. We therefore investigated the effect of mammalian target of rapamycin (mTOR) inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on human T-cell leukemia virus type 1 (HTLV-1)-infected-cell and ATL-cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1-phase cell-cycle arrest and subsequent cell apoptosis, whereas the effects of the 2 mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL-cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine-473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL-cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL-cell proliferation and might thus be a new therapeutic target in ATL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Everolimus/administration & dosage , Everolimus/pharmacology , Humans , Indoles/administration & dosage , Indoles/pharmacology , Leukemia-Lymphoma, Adult T-Cell/metabolism , Mice , Morpholines/administration & dosage , Morpholines/pharmacology , Phosphorylation/drug effects , Purines/administration & dosage , Purines/pharmacology , RNA, Small Interfering/genetics , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/pharmacology , Xenograft Model Antitumor AssaysSubject(s)
Aniline Compounds/therapeutic use , Bone Marrow Neoplasms/drug therapy , Bone Marrow Neoplasms/secondary , Leukemia, Myeloid, Acute/drug therapy , Oligopeptides/therapeutic use , Prostatic Neoplasms/pathology , Pyrazines/therapeutic use , Bone Marrow Neoplasms/genetics , Bone Marrow Neoplasms/pathology , Gonadotropin-Releasing Hormone/agonists , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation/drug effects , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
We had two cases of trisomy 8-positive myelodysplastic syndrome (MDS) with incomplete Behçet's disease (BD) in which the remissions of both diseases were maintained by allogeneic stem cell transplantation (allo-SCT). Among MDS with BD patients, sometimes it is difficult to control the symptoms of BD with standard therapies such as corticosteroids and tumor necrosis factor (TNF) inhibitors. Although there should be careful consideration regarding indications for transplantation, our two cases, in which refractory BD was completely controlled by allo-SCT, suggest that allo-SCT can be one of the treatment options for higher-risk MDS with BD patients.
Subject(s)
Behcet Syndrome , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes , Behcet Syndrome/complications , Behcet Syndrome/diagnosis , Behcet Syndrome/therapy , Chromosomes, Human, Pair 8 , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/therapy , TrisomyABSTRACT
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal large B-cell lymphoma characterized by the growth of lymphoma cells only within the lumina of small vessels in various organs. IVLBCL is an intractable hematological disease, in particular, the high incidence of central nervous system (CNS) involvement is one of the causes of the poor prognosis of IVLBCL. Autologous stem cell transplantation (ASCT) is an effective therapeutic option for refractory or high-risk aggressive lymphoma. However, it is unknown whether ASCT is an effective treatment for CNS involvement of aggressive lymphoma including IVLBCL. We show a case of a 39-year-old woman with recurrent CNS involvement of IVLBCL receiving autologous peripheral blood stem cell transplantation (auto-PBSCT) preconditioned with high-dose thiotepa, busulfan, cyclophosphamide (TBC regimen). Culture-negative febrile neutropenia developed requiring antimicrobial therapy, but nonhematological adverse effects including stomatitis and neurotoxicity, with grade ≥ 3, were not observed. The patient achieved and has maintained complete remission (CR) for 24 months after TBC/auto-PBSCT and has survived for around 30 months from the diagnosis of the CNS recurrence. The clinical course of this case suggests that auto-PBSCT preconditioned with TBC could be one of the therapeutic options for the treatment of CNS involvement of IVLBCL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Peripheral Blood Stem Cell Transplantation , Vascular Neoplasms/therapy , Adult , Antineoplastic Agents, Alkylating/administration & dosage , Busulfan/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Female , Humans , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Remission Induction , Thiotepa/administration & dosage , Transplantation, HomologousABSTRACT
This is the first report of a case of COVID-19 after allogeneic stem cell transplantation. Our case suggests that COVID-19 may exist without characteristic CT images, especially in immunocompromised hosts, such as patients after transplantation.
ABSTRACT
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site. Overexpression of NRF-1 increased TDP1-promoter activity, whereas the introduction of dominant-negative NRF-1 repressed such activity. Overexpression of NRF-1 also upregulated endogenous TDP-1 expression, while introduction of shNRF-1 suppressed TDP1 in Jurkat T cells, making them susceptible to abacavir. These results indicate that NRF-1 is a positive transcriptional regulator of TDP1-gene expression. Importantly, we revealed that HTLV-1 bZIP factor (HBZ) protein which is expressed in all ATL cases physically interacts with NRF-1 and inhibits the DNA-binding ability of NRF-1. Taken together, HBZ suppresses TDP1 expression by inhibiting NRF-1 function in ATL cells. The HBZ/NRF-1/TDP1 axis provides new therapeutic targets against ATL and might explain genomic instability leading to the pathogenesis of ATL.
Subject(s)
Basic-Leucine Zipper Transcription Factors/metabolism , Human T-lymphotropic virus 1/metabolism , Leukemia-Lymphoma, Adult T-Cell/metabolism , Nuclear Respiratory Factor 1/metabolism , Phosphoric Diester Hydrolases/genetics , Retroviridae Proteins/metabolism , Adult , Base Sequence , Basic-Leucine Zipper Transcription Factors/genetics , DNA/metabolism , HEK293 Cells , Humans , Jurkat Cells , Phosphoric Diester Hydrolases/metabolism , Promoter Regions, Genetic/genetics , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , Retroviridae Proteins/genetics , Transcription, GeneticSubject(s)
Lymphoma, Large B-Cell, Diffuse/diagnosis , Aged , Bone Marrow Examination/methods , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.
ABSTRACT
Vif is essential for HIV-1 replication in T cells and macrophages. Vif recruits a host ubiquitin ligase complex to promote proteasomal degradation of the APOBEC3 restriction factors by poly-ubiquitination. The cellular transcription cofactor CBFß is required for Vif function by stabilizing the Vif protein and promoting recruitment of a cellular Cullin5-RING ubiquitin ligase complex. Interaction between Vif and CBFß is a promising therapeutic target, but little is known about the interfacial residues. We now demonstrate that Vif conserved residues E88/W89 are crucial for CBFß binding. Substitution of E88/W89 to alanines impaired binding to CBFß, degradation of APOBEC3, and virus infectivity in the presence of APOBEC3 in single-cycle infection. In spreading infection, NL4-3 with Vif E88A/W89A mutation replicated comparably to wild-type virus in permissive CEM-SS cells, but not in multiple APOBEC3 expressing non-permissive CEM cells. These results support a model in which HIV-1 Vif residues E88/W89 may participate in binding CBFß.
Subject(s)
Core Binding Factor beta Subunit/metabolism , HIV Infections/metabolism , HIV-1/metabolism , vif Gene Products, Human Immunodeficiency Virus/chemistry , vif Gene Products, Human Immunodeficiency Virus/metabolism , Amino Acid Motifs , Amino Acid Sequence , Conserved Sequence , Core Binding Factor beta Subunit/genetics , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , HIV Infections/enzymology , HIV Infections/genetics , HIV Infections/virology , HIV-1/chemistry , HIV-1/genetics , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Binding , vif Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling.