Abstract:
:Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500 nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.
journal_name
Bloodjournal_title
Bloodauthors
Ranganathan P,Yu X,Na C,Santhanam R,Shacham S,Kauffman M,Walker A,Klisovic R,Blum W,Caligiuri M,Croce CM,Marcucci G,Garzon Rdoi
10.1182/blood-2012-04-423160subject
Has Abstractpub_date
2012-08-30 00:00:00pages
1765-73issue
9eissn
0006-4971issn
1528-0020pii
blood-2012-04-423160journal_volume
120pub_type
杂志文章相关文献
BLOOD文献大全abstract::The study of chemoattractant receptors on human monocytes had been limited by the lack of a radioligand suitable for use with the small numbers of cells routinely available from human donors. A new synthetic oligopeptide radioligand f[35S]met-leu-phe, with a higher specific radioactivity than was available with the tr...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1984-03-01 00:00:00
abstract::While studying patient plasma containing an unusual pattern of von Willebrand factor (VWF) multimers, we discovered a previously unreported phenomenon: heavy predominance of dimeric VWF. Genomic analysis revealed a new congenital mutation (Tyr87Ser) that altered the final stages of VWF biosynthesis. This mutation in t...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-03-0789
更新日期:2002-09-01 00:00:00
abstract::Steroid-resistant or steroid-refractory acute graft-versus-host disease (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field has been driven by the premise that persistent graft-ver...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.2019000960
更新日期:2020-05-07 00:00:00
abstract::Stimulators of human erythroid burst-forming units (BFU-E) and multipotential colony-forming cells (CFU-GEMM) can be produced by a number of different cell types. A product of human peripheral blood monocytes, interleukin 1 (IL-1), was evaluated for its ability to stimulate fibroblast cultures to produce stimulators o...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1987-01-01 00:00:00
abstract::The role of interleukin-12 (IL-12) in Th1 cell differentiation is well established. The heterodimer p70, composed of a p40 and a p35 chain, is the biologically active form. IL-12 production by human monocytes is enhanced by interferon-gamma (IFN-gamma) and inhibited by IL-10 and prostaglandin E2 (PGE2). Peripheral blo...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-01-15 00:00:00
abstract::Platelets play a crucial role in the physiology of primary hemostasis and pathophysiologic processes such as arterial thrombosis. Accumulating evidence suggests a role of reactive oxygen species (ROSs) in platelet activation. Here we show that platelets activated with different agonists produced intracellular ROSs, wh...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-03-1047
更新日期:2005-10-15 00:00:00
abstract::The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) C...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-01-690743
更新日期:2016-08-04 00:00:00
abstract::The Augustine-negative alias At(a-) blood type, which seems to be restricted to people of African ancestry, was identified half a century ago but remains one of the last blood types with no known genetic basis. Here we report that a nonsynonymous single nucleotide polymorphism in SLC29A1 (rs45458701) is responsible fo...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2015-03-631598
更新日期:2015-06-04 00:00:00
abstract::The effect of high-dose chemotherapy and autografting on bone turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), exp...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-10-15 00:00:00
abstract::Development of acute graft-versus-host disease (aGVHD) predisposes to chronic GVHD with autoimmune manifestations. A characteristic of experimental aGVHD is the de novo generation of autoreactive T cells. Central tolerance is dependent on the intrathymic expression of tissue-restricted peripheral self-antigens (TRA), ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-12-474759
更新日期:2013-08-01 00:00:00
abstract::Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2014-09-600643
更新日期:2015-04-09 00:00:00
abstract::Epinephrine causes platelet aggregation and secretion by interacting with alpha 2-adrenergic receptors on the platelet surface. Platelet aggregation requires the binding of fibrinogen to a specific receptor on the membrane glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is identifiable on the surface of r...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::Natural-killer (NK)-cell dysfunction and IFN-gamma deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, br...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-11-4535
更新日期:2006-07-01 00:00:00
abstract::Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that kn...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-10-248526
更新日期:2010-05-20 00:00:00
abstract::Most patients with acute myeloid leukemia (AML) enter complete remission (CR) after treatment with chemotherapy, but a large number of them experience relapse with resistant disease. To identify genes that are associated with their prognoses, we analyzed gene expression in 54 pediatric patients with AML using an oligo...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-02-0578
更新日期:2003-09-01 00:00:00
abstract::Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo iso...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-03-341917
更新日期:2011-07-14 00:00:00
abstract::Nitric oxide (NO) is a potent radical produced by nitric oxide synthase (NOS) and has pleiotrophic activities in health and disease. As mast cells (MCs) play a central role in both homeostasis and pathology, we investigated NOS expression and NO production in human MC populations. Endothelial NOS (eNOS) was ubiquitous...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-08-2990
更新日期:2004-07-15 00:00:00
abstract::High molecular weight (HMW) kininogen, the cofactor for activation of the contact system of plasma proteolysis, transports and optimally positions prekallikrein and factor XI on a negatively charged surface, allowing those zymogens to be activated by surface-bound factor XIIa. HMW kininogen circulates in plasma as a p...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::High-pressure liquid chromatography analysis of polyamines in bone narrow from leukemic and nonleukemic subjects demonstrated increased concentrations of putrescine, spermidine, and spermine associated with increased cellularity. The most striking abnormality was the marked elevation of putrescine. Bone marrow polyami...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1976-04-01 00:00:00
abstract::Hematologic engraftment and immune reconstitution were examined in patients who received cyclophosphamide and total body irradiation therapy followed by infusion of autologous bone marrow purged with anti-B1 monoclonal antibody (MoAb) and complement as therapy for non-Hodgkin's lymphoma. Hematologic engraftment was pr...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2014-06-580340
更新日期:2015-01-01 00:00:00
abstract::A 64-yr-old female developed acute myeloblastic leukemia following radiation and drug therapy for colon carcinoma. The patient was heterozygous for glucose-6-phosphate dehydrogenase (G-6-PD) and displayed types A and B isoenzymes in nonhematopoietic tissue. In contrast, only type B G-6-PD was observed in peripheral bl...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1978-10-01 00:00:00
abstract::In vitro models of granulopoiesis involving the inducible expression of either CCAAT enhancer binding protein alpha (C/EBP alpha) or C/EBP epsilon in myeloid cells have been shown to lead to the induction of a granulocytic maturation program accompanied by the expression of myeloid-specific genes. Since members of the...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-09-2767
更新日期:2003-05-01 00:00:00
abstract::P-selectin expression has been shown in Helicobacter pylori-infected persons, an infection that has been clinically associated with platelet-related diseases, such as idiopathic thrombocytopenic purpura. However, the role of P-selectin expression during H pylori infection remains unclear. In this study, we hypothesize...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-09-241166
更新日期:2010-05-27 00:00:00
abstract::In children with acute lymphoblastic leukemia (ALL), the level of minimal residual disease (MRD) at the end of induction strongly predicts outcome, presumably because it measures both drug sensitivity and the number of leukemic cells requiring elimination. Children with high levels (> 10(-3) leukemic cells per marrow ...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究
doi:
更新日期:1996-06-15 00:00:00
abstract::The relationship between platelet density and platelet age appears to vary between species with relatively few labeling studies in humans reported. In this study, irreversible monoamine oxidase (MAO) inhibitors were used to biochemically label the circulating platelet population in 15 humans. Platelet samples were the...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
abstract::The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compa...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1989-06-01 00:00:00
abstract::Regulatory molecules produced by stromal cells are often membrane bound until cleaved by matrix metalloproteinases (MMPs); cleavage can either activate or inactivate regulatory functions. We report here that marrow stromal cells induce the expression of MMP-9 in monocytes. Induction was contact independent and could b...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-05-020289
更新日期:2007-01-01 00:00:00
abstract::Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international no...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-03-1108
更新日期:2005-10-01 00:00:00
abstract::We treated 5 patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and multifocal bone lesions or diffuse bone marrow plasmacytic infiltration with high-dose therapy (HDT) and autologous blood stem cell transplantation. In all cases, the treatment produced...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood.v99.8.3057
更新日期:2002-04-15 00:00:00