Abstract:
:The transcription factor nuclear factor-kappaB (NF-kappaB) confers significant survival potential in a variety of tumors. Several established or novel anti-multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-kappaB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-kappaB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-kappaB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochrome c release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) is present locally in the bone marrow microenvironment and induces NF-kappaB-dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-alpha alone induced NF-kappaB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-alpha-induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-alpha family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-alpha-induced expression of another NF-kappaB target gene, intercellular adhesion molecule-1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-kappaB pathways. Our results therefore demonstrate that NF-kappaB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-kappaB activity in novel biologically based therapies for MM.
journal_name
Bloodjournal_title
Bloodauthors
Mitsiades N,Mitsiades CS,Poulaki V,Chauhan D,Richardson PG,Hideshima T,Munshi N,Treon SP,Anderson KCdoi
10.1182/blood.v99.11.4079subject
Has Abstractpub_date
2002-06-01 00:00:00pages
4079-86issue
11eissn
0006-4971issn
1528-0020journal_volume
99pub_type
杂志文章相关文献
BLOOD文献大全abstract::The TEL/PDGFbetaR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFbetaR is invariably associated with a myeloid leukemia phenot...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-03-01 00:00:00
abstract::Twenty consecutive patients with Hodgkin disease in continuous complete remission and off treatment for at least 5 yr (range 5-25 yr, median 9 yr) were studied with a battery of immunologic parameters. Skin test reactivity to four common antigens, sensitization to 2,4-dinitrochlorobenzene, absolute lymphocyte count, r...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1977-05-01 00:00:00
abstract::To determine whether a prior history of hepatosplenic candidiasis resulted in increased Candida-associated morbidity and mortality after marrow transplant, 15 consecutive patients with biopsy-proven hepatosplenic candidiasis were observed prospectively. All patients received amphotericin B before transplant. Amphoteri...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-10-15 00:00:00
abstract::Unstained human eosinophils exhibit unusually bright autofluorescence, which allows them to be distinguished from other leukocytes using fluorescence microscopy. Eosinophil fluorescence is associated with the cytoplasmic granules of the cells. Eosinophil granule extracts, containing an as-yet-undefined eosinophil fluo...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1981-06-01 00:00:00
abstract::Mutations in PIEZO1 are the primary cause of hereditary xerocytosis, a clinically heterogeneous, dominantly inherited disorder of erythrocyte dehydration. We used next-generation sequencing-based techniques to identify PIEZO1 mutations in individuals from 9 kindreds referred with suspected hereditary xerocytosis (HX) ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2017-05-786004
更新日期:2017-10-19 00:00:00
abstract::The prevalence of anti-hepatitis C virus (HCV) enzyme immunoassay (EIA)-positive in 167,511 Australian volunteer blood donors from Adelaide, Melbourne, Perth, and Sydney was 0.78%. One thousand two-hundred and eighteen EIA-positive serum samples were assessed by supplemental tests including a blocking EIA and two pept...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-11-01 00:00:00
abstract::Hematopoietic stem cell (HSC) homeostasis is controlled by cytokine receptor-mediated Janus kinase 2 (JAK2) signaling. We previously found that JAK2 is promptly ubiquitinated upon cytokine stimulation. Whether a competing JAK2 deubiquitination activity exists is unknown. LNK is an essential adaptor protein that constr...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2018-10-877563
更新日期:2019-04-04 00:00:00
abstract::In this issue of Blood, Jitschin et al demonstrate a microenvironmental glycolytic shift in chronic lymphocytic leukemia (CLL) cells mediated by Notch-c-Myc signaling. Interfering in the Notch-c-Myc pathway and reprogramming glycolytic metabolism could contribute to overcoming drug resistance in CLL. ...
journal_title:Blood
pub_type: 评论,杂志文章
doi:10.1182/blood-2015-04-636332
更新日期:2015-05-28 00:00:00
abstract::The three-dimensional tertiary structure of human von Willebrand Factor (vWF) on a hydrophobic surface under aqueous conditions and different shear stress regimes was studied by atomic force microscopy (AFM). vWF was imaged by AFM at molecular level resolution under negligible shear stress, under a local applied shear...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-10-15 00:00:00
abstract::A 72-yr-old male with a lifelong history of easy bruisability and posttraumatic bleeding had a prolonged prothrombin time and activated partial thromboplastin time. His plasma Stypven, Taipan, and Echis carinatus venom clotting times were prolonged. The presence of a dysprothrombin was confirmed by the discrepancy bet...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1980-05-01 00:00:00
abstract::Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-07-034157
更新日期:2007-05-01 00:00:00
abstract::In eighty-three patients with confirmed deep vein thrombosis, the fibrinolytic system was studied before and after a 10-minute venous occlusion. Blood was collected at least 3 months after the last acute episode, and PAI-1 antigen and activity, as well as tissue-type plasminogen activator (t-PA) antigen, urokinase-typ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::The leukemia-specific AML1/ETO fusion gene has been shown to be detected by reverse transcriptase polymerase chain reaction (RT-PCR) analysis in patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. In the present study, the AML1/ETO mRNA could be detected by RT-PCR in bone marrow (BM) and/or ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
abstract::Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)-infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-i...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study,...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2013-02-483263
更新日期:2013-09-12 00:00:00
abstract::Heme biosynthesis was examined in erythroid tissue of a 4-yr-old girl with severe sideroblastic anemia since infancy, as documented by the presence of intramitochondrial deposits of iron in erythroblasts. Free red cell protoporphyrin, urinary porphyrins, and activities of erythrocyte porphobilinogen synthase, uroporph...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1980-01-01 00:00:00
abstract::Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (bet...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-04-15 00:00:00
abstract::We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is rep...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1182/blood-2002-02-0632
更新日期:2002-12-15 00:00:00
abstract::Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell-related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy h...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-03-344051
更新日期:2011-10-20 00:00:00
abstract::Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identifi...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2008-06-165266
更新日期:2009-02-05 00:00:00
abstract::FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in acute myeloid leukemia (AML). We tested the sensitivity of 8 activation loop mutations to the small molecule FLT3 inhibitor, MLN518. Each FLT3 activation loop mutant, including D835Y, ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-12-4446
更新日期:2004-11-01 00:00:00
abstract::Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide ...
journal_title:Blood
pub_type: 杂志文章,meta分析
doi:10.1182/blood-2011-10-383380
更新日期:2012-01-26 00:00:00
abstract::The interaction of factor VIII with von Willebrand factor (vWF) was investigated on a quantitative and qualitative level. Binding characteristics were determined using a solid phase binding assay and protection of factor VIII by vWF from inactivation by activated protein C (aPC) was studied using three different assay...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-03-15 00:00:00
abstract::In this study, the question of whether glycoprotein Ib (GPIb) mediates both high and moderate affinity pathways of alpha-thrombin-induced platelet activation was examined. Flow cytometric studies, using a panel of monoclonal antibodies (MoAbs), showed that Serratia marcescens protease treatment removed greater than 97...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-04-15 00:00:00
abstract::Recent studies have reported that the pharmacokinetics of high-dose busulfan in bone marrow transplantation (BMT) are age-dependent: with the usual dosage of 16 mg/kg over 4 days, systemic exposure is two to four times lower in children than in adults. Data suggested that the dose of busulfan should rather be calculat...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::Noncovalent association between the von Willebrand factor (VWF) propeptide (VWFpp) and mature VWF aids N-terminal multimerization and protein compartmentalization in storage granules. This association is currently thought to dissipate after secretion into blood. In the present study, we examined this proposition by qu...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-10-387548
更新日期:2012-05-17 00:00:00
abstract::Integrin-β7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-β7 in MM are largely unknown. C...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-06-292243
更新日期:2011-06-09 00:00:00
abstract::It was found in a long-term bromodeoxyuridine (BrdU) infusion study that two or more different subpopulations of bone marrow stem cells exist in mice. One of these subpopulations appears to be noncycling and forms approximately 10% of eight-day CFU-S. Another one, a subpopulation of slowly cycling bone marrow cells, i...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-12-01 00:00:00
abstract::Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixt...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究
doi:
更新日期:1995-11-01 00:00:00
abstract::The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2018-05-852566
更新日期:2018-10-04 00:00:00