Abstract:
:Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.
journal_name
Br J Haematoljournal_title
British journal of haematologyauthors
Mishima Y,Santo L,Eda H,Cirstea D,Nemani N,Yee AJ,O'Donnell E,Selig MK,Quayle SN,Arastu-Kapur S,Kirk C,Boise LH,Jones SS,Raje Ndoi
10.1111/bjh.13315subject
Has Abstractpub_date
2015-05-01 00:00:00pages
423-34issue
3eissn
0007-1048issn
1365-2141journal_volume
169pub_type
杂志文章abstract::Venesection of 10% of whole blood volume or plateletpheresis was performed in nine patients with chronic myeloproliferative disorders and in five normal control subjects. Before venesection, the patients showed impaired platelet aggregation in 33% of tests, most often in response to stimulation with 9 mumol adrenaline...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1978.tb03629.x
更新日期:1978-08-01 00:00:00
abstract::The present study analysed whether autologous peripheral blood stem cell transplantation (PSCT) improves engraftment, quality of life and cost-effectiveness when compared with autologous bone marrow transplantation (ABMT). Relapsing progressive lymphoma patients (n = 204; non-Hodgkin's lymphoma n = 166; Hodgkin's dise...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1046/j.1365-2141.2001.02926.x
更新日期:2001-08-01 00:00:00
abstract::The transforming growth factor-beta-related factor bone morphogenetic protein 4 (BMP4) is expressed in the human embryonic aorta-gonad-mesonephros (AGM) coincident with the emergence of haematopoietic cells and influences postnatal mammalian haematopoietic stem cells in vitro. To investigate the role of BMP4 in mammal...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2007.06795.x
更新日期:2007-10-01 00:00:00
abstract::Persistent lymphocytosis is usually associated with a malignant lymphoproliferative disease (MLPD). We report six female patients presenting a chronic, moderate lymphocytosis of 2-16 years duration with atypical binucleated lymphocytes on peripheral blood smears. Further investigation showed a polyclonal increase in s...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb05018.x
更新日期:1994-10-01 00:00:00
abstract::Myeloproliferative disorders (MPD) are reported in 25-65% of patients with splanchnic vein thrombosis (SVT). Diagnostic criteria for MPD have not been fully established in this context. Using clusters of abnormal megakaryocytes in bone marrow (BM) biopsy as a reference standard for Philadelphia negative MPD, we assess...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2005.05490.x
更新日期:2005-05-01 00:00:00
abstract::Data on endogenous thrombopoietin (TPO) levels and their regulation in myelodysplastic syndromes (MDS) are sparse. We examined the plasma TPO level of 85 MDS patients by a sensitive enzyme immunoassay and the platelet expression of TPO receptor (TPO-R) protein, which metabolizes endogenous TPO, in 19 MDS patients with...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.01054.x
更新日期:1998-12-01 00:00:00
abstract::Distinguishing Burkitt lymphoma (BL) from B cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL (DLBCL/BL), and DLBCL is challenging. We propose an immunohistochemistry and fluorescent in situ hybridization (FISH) based scoring system that is employed in three ...
journal_title:British journal of haematology
pub_type: 杂志文章,多中心研究
doi:10.1111/j.1365-2141.2011.08771.x
更新日期:2011-09-01 00:00:00
abstract::A simple rapid platelet aggregation test was used to evaluate cross-reactivity of four low molecular weight heparins and the heparinoid ORG 10172 in three patients with heparin-induced thrombocytopenia. The low molecular weight heparins cross-reacted in 11 out of 12 tests. The heparinoid ORG 10172 did not cross-react ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb04760.x
更新日期:1994-02-01 00:00:00
abstract::Simultaneous evaluation of coagulation and fibrinolysis facilitates an overall understanding of normal and pathological haemostasis. We established an assay for assessing clot formation and fibrinolysis simultaneously using clot waveform analysis by the trigger of a mixture of activated partial thromboplastin time rea...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.16111
更新日期:2019-11-01 00:00:00
abstract::A child of Italian origin with a congenital haemolytic anaemia had spectrophotometrically undetectable erythrocyte adenylate kinase (AK) activity. Her parents and brother had approximately 50% normal AK activity, and AK electrophoresis of red blood cell (RBC) crude extract on cellulose acetate strips showed the presen...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.4953299.x
更新日期:1997-12-01 00:00:00
abstract::We have identified a novel polymorphism located in intron 1a of the human factor VII gene, caused by the nucleotide change G to A at position + 73. In a population of 128 healthy individuals from northern Italy, the variant A73 allele had a frequency of 0.21, whereas the frequency of the previously reported 10 bp inse...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.01833.x
更新日期:2000-02-01 00:00:00
abstract::Parental longevity is associated with an increased life expectancy; results with regard to specific diseases are conflicting. There are limited data focusing on host characteristics and their effect on survival among multiple myeloma (MM) patients and individuals with monoclonal gammopathy of undetermined significance...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.15883
更新日期:2019-07-01 00:00:00
abstract::Deficiency in DNA repair capability is considered to be responsible for oncogenesis. Hereditary and sporadic cancers in various tissues have been reported to have mutations at the DNA repair genes. In this study we analysed two excision repair genes (ERCC1 and XPCC) and two mismatch repair genes (hMSH2 and hMTH1) in t...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00973.x
更新日期:1998-11-01 00:00:00
abstract::In 1997, the Italian Ministry of Health created a special programme for the controlled distribution of deferiprone to collect data and to evaluate its safety and effectiveness in long-term use. Five hundred and thirty-two thalassaemia patients from 86 treatment centres were enrolled in this programme. One hundred and ...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1046/j.1365-2141.2002.03554.x
更新日期:2002-07-01 00:00:00
abstract::Patients with solid tumours undergoing high-dose chemotherapy with autologous bone marrow transplantation use an average of 10 units of packed red blood cells (PRBC) while awaiting haemopoietic reconstitution. They are also known to have inappropriately low endogenous erythropoietin levels for their degree of anaemia....
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2141.1994.tb04886.x
更新日期:1994-05-01 00:00:00
abstract::A 69-year-old woman presented with splenic marginal zone lymphoma associated with acquired von Willebrand's disease (AVWD). Laboratory abnormalities included markedly decreased plasma levels of factor VIII coagulant (C) activity (VIII:C 28%), von Willebrand's factor (VWF) antigen (Ag) (vWF:Ag < 6%), and VWF ristocetin...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.d01-2088.x
更新日期:1997-03-01 00:00:00
abstract::A systematic analysis of the blast cell population was carried out on samples from 50 patients suffering from blast transformation of chronic granulocytic leukaemia (CGL) (31) and of myelofibrosis (4), acute myelofibrosis (AM) (11) and undifferentiated acute leukaemia (4). Transmission electron microscopy (TEM), used ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1985.tb02994.x
更新日期:1985-02-01 00:00:00
abstract::Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2009.07728.x
更新日期:2009-07-01 00:00:00
abstract::About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe and ...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1046/j.1365-2141.1999.01693.x
更新日期:1999-11-01 00:00:00
abstract::Systemic inflammation activates the tissue factor/factor VIIa complex (TF/FVIIa), leading to a procoagulant state, which may be enhanced by impairment of physiological anticoagulant pathways, such as the protein C system. Besides impaired protein C activation, resistance to activated protein C (APC) may occur. We stud...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2006.06127.x
更新日期:2006-07-01 00:00:00
abstract::During a trial using recombinant human interleukin-2 (rhIL-2) immunotherapy for acute myeloblastic leukaemia (AML) in remission, eosinophilia was observed in all patients. We used in-vitro clonogenic assays to investigate the mechanism of the eosinophilia in five patients. The mean eosinophil count increased from 0.05...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1990.tb07867.x
更新日期:1990-10-01 00:00:00
abstract::The Dutch beta zero-thalassaemia has few clinical symptoms in homozygotes, elevated fetal haemoglobin (4-11%) in heterozygotes, and has a DNA deletion previously estimated as 10 kb which removes the beta-globin gene (Gilman et al, 1984). A DNA fragment containing the breakpoints of the Dutch beta zero-thalassaemia del...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1987.tb02360.x
更新日期:1987-11-01 00:00:00
abstract::Between 1984 and 1992, 21 patients with chronic myeloid leukaemia (CML) in chronic phase (CP) were treated with high-dose chemotherapy (or chemoradiotherapy) followed by autografting with unmanipulated peripheral blood stem cells (PBSC). 12 of these patients survive at a median of 82 months from the time of autografti...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb03255.x
更新日期:1994-01-01 00:00:00
abstract::Recently, leukaemia-associated antigens (LAA) recognized by T lymphocytes, such as Wilm's tumour-1 (WT-1) or pathogenesis-related protein-1 (PR-1), have been identified. For immunotherapies that employ antigen peptides, either alone or pulsed on dendritic cells (DC), the expression of human leucocyte antigen (HLA) mol...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2003.04212.x
更新日期:2003-03-01 00:00:00
abstract::During the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) or granulocyte-macrophage CSF (rhGM-CSF) we studied the early and late changes of membrane antigen density on neutrophils. RhG-CSF and rhGM-CSF both caused an early transient reduction in blood neutrophilic granulocyte-conce...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1993.tb08644.x
更新日期:1993-09-01 00:00:00
abstract::Sixty patients with haematological malignancies received a myeloablative regimen of total body irradiation, cyclophosphamide and fludarabine followed by a T-cell-depleted peripheral blood stem cell transplant from a human leucocyte antigen identical sibling. To improve donor immune function, 1 x 10(7) CD3+ cells/kg we...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2005.05665.x
更新日期:2005-09-01 00:00:00
abstract::A reduction of donor effects during centrifugal plateletpheresis with the Haemonetics Blood Processor was achieved by reducing the concentration of the citrate anticoagulant. Serum citrate and ionized calcium levels, immediately and 1 h post-pheresis, were affected to a lesser extent by using 5.0 g total ionized citra...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1976.tb03585.x
更新日期:1976-11-01 00:00:00
abstract::Clusters and chains of basophilic micro-organisms were found on the red cells of a woman who suffered from malignant melanoma. The infection was clinically silent for at least 7 years. During her last year of life the patient became febrile and anaemic. Her spleen enlarged and the basophilic bodies on her red cells be...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1975.tb01824.x
更新日期:1975-02-01 00:00:00
abstract::Multiple myeloma (MM) is currently incurable, and novel therapies are needed. In this study, we examined a novel recombinant humanized monoclonal antibody against CD40 (rhuCD40 mAb) and demonstrate for the first time that rhuCD40 mAb induces antibody-dependent cell-mediated cytotoxicity (ADCC) against CD40-positive MM...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2003.04322.x
更新日期:2003-05-01 00:00:00
abstract::The platelet-sized particle formation in the human megakaryoblastic leukaemia cell line MEG-01 and its subline MEG-01s was examined. MEG-01 and MEG-01s cells spontaneously released platelet-sized particles into the culture medium, in which the cells occasionally extended cytoplasmic processes similar to those of megak...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00576.x
更新日期:1998-02-01 00:00:00