Abstract:
:The molecular basis of different outcomes in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionizing radiation (IR)-induced DNA double-strand breaks in 74 pediatric patients with ALL. We found an apoptosis-resistant response in 36% of patients characterized by failure to cleave caspase-3, -7, -9, and PARP1 by 24 hours after IR and an apoptosis-sensitive response with the cleavage of the same substrates in the remaining 64% of leukemias. Resistance to IR in vitro was associated with poor early blast clearance at day 7 or 15 and persistent minimal residual disease (MRD) at day 28 of induction treatment. Global gene expression profiling revealed abnormal up-regulation of multiple prosurvival pathways in response to IR in apoptosis-resistant leukemias and differential posttranscriptional activation of the PI3-Akt pathway was observed in representative resistant cases. Importantly, pharmacologic inhibition of selected prosurvival pathways sensitized apoptosis-resistant ALL cells to IR in vitro. We suggest that abnormal prosurvival responses to DNA damage provide one of the mechanisms of primary resistance in ALL, and that they should be considered as therapeutic targets in children with aggressive disease.
journal_name
Bloodjournal_title
Bloodauthors
Marston E,Weston V,Jesson J,Maina E,McConville C,Agathanggelou A,Skowronska A,Mapp K,Sameith K,Powell JE,Lawson S,Kearns P,Falciani F,Taylor M,Stankovic Tdoi
10.1182/blood-2008-03-142950subject
Has Abstractpub_date
2009-01-01 00:00:00pages
117-26issue
1eissn
0006-4971issn
1528-0020pii
blood-2008-03-142950journal_volume
113pub_type
杂志文章相关文献
BLOOD文献大全abstract::The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-07-233445
更新日期:2010-01-28 00:00:00
abstract::To test the efficacy of poststorage bedside leucodepletion of blood products in the prevention of primary HLA alloimmunization and its clinical sequelae, 172 patients with hematologic malignancy requiring intensive red blood cell and platelet support were randomized to receive either standard or filtered red blood cel...
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:
更新日期:1994-05-15 00:00:00
abstract::Using urea-solubilized human fibrin monomer as an immunogen, we raised in mice a battery of monoclonal antibodies that reacted with the immunogen but not with urea-treated or native fibrinogen. Although they all failed to react with acid-solubilized fibrin monomer (acid-FM) alone, an antibody designated as IF-43 was f...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-09-15 00:00:00
abstract::The coagulation factors V (FV) and VIII (FVIII) are important at sites of vascular injury for the amplification of the clotting cascade. Natural variants of these factors frequently lead to severe bleeding disorders. To understand the mechanisms of activation of FVIII by thrombin, we used a bank of mutant thrombins to...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-03-0843
更新日期:2002-10-15 00:00:00
abstract::Phospholipase C (PLC)-mediated hydrolysis of membrane phospholipids results in the production of diacylglycerol, inositol phosphates, and choline metabolites. Inositol triphosphate increases calcium levels, while diacylglycerol activates protein kinase C. The present studies demonstrate that exogenous PLC generates in...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::Because free factor VIIa is inactivated only very slowly by a plasma concentration of antithrombin III (AT III) even in the presence of heparin, it has been assumed that AT III plays no significant role in regulating the initiation of tissue factor-dependent blood coagulation. However, in the present study, we present...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-05-15 00:00:00
abstract::Telomere length has been linked to disease stage and degree of (pan-)cytopenia in patients with bone marrow failure syndromes. The aim of the current study was to analyze the impact of replicative stress on telomere length in residual glycosylphosphatidylinositol-positive (GPI+) versus GPI- hematopoiesis in patients w...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2004-10-3996
更新日期:2005-07-15 00:00:00
abstract::Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-05-431791
更新日期:2012-09-27 00:00:00
abstract::Elevated levels of interleukin 7 (IL-7) have been correlated with various T-cell depletion conditions, including HIV infection, and suggested as an indicator of HIV disease progression (AIDS and death). Here, the assessment of pathogenic simian immunodeficiency virus (SIVmac239) infection in rhesus macaques demonstrat...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-03-0874
更新日期:2004-02-01 00:00:00
abstract::Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who disc...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2004-01-0200
更新日期:2004-12-01 00:00:00
abstract::We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK(+) patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK(+)....
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2011-07-367508
更新日期:2012-01-12 00:00:00
abstract::Enteropathy-associated T-cell lymphoma (EATL) is a rare subtype of peripheral T-cell lymphomas with a poor prognosis. Autologous stem cell transplantation (ASCT) was retrospectively evaluated as a consolidation or salvage strategy for EATL. The analysis included 44 patients who received ASCT for EATL between 2000 and ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-11-466839
更新日期:2013-03-28 00:00:00
abstract::In vitro agar culture patterns of bone marrow cells in acute myeloid leukemia may show several growth patterns, including cultures where no colonies or clusters develop, cultures with varying numbers of clusters and no colonies, or colony and cluster formation with an extremely high ratio of clusters to colonies. Twel...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1979-08-01 00:00:00
abstract::Unfractionated heparin (UFH) is a widely used anticoagulant that has long been known to potentiate platelet responses to subthreshold doses of platelet agonists. UFH has been reported to bind and induce modest conformational changes in the major platelet integrin, αIIbβ3, and induce minor changes in platelet morpholog...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-09-307751
更新日期:2011-05-05 00:00:00
abstract::To test the hypothesis that skeletal muscle myosins can directly influence blood coagulation and thrombosis, ex vivo studies of the effects of myosin on thrombogenesis in fresh human blood were conducted. Addition of myosin to blood augmented the thrombotic responses of human blood flowing over collagen-coated surface...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-03-707679
更新日期:2016-10-06 00:00:00
abstract::The bcl-2 gene is translocated into the Ig loci in about 80% of human follicular lymphomas and in 10% of B-type chronic lymphocytic leukemias (B-CLL), resulting in a high level of expression. We have compared the expression of bcl-2 transcripts and protein in B-CLL cells in their normal equivalent CD5+ B cells and in ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-06-01 00:00:00
abstract::Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredun...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-09-381012
更新日期:2012-03-01 00:00:00
abstract::Erythropoietin (Epo) binding to the Epo receptor (EpoR) elicits downstream signaling that is essential for red blood cell production. One important negative regulatory mechanism to terminate Epo signaling is Epo-induced EpoR endocytosis and degradation. Defects in this mechanism play a key role in the overproduction o...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2013-05-506212
更新日期:2013-12-05 00:00:00
abstract::Immunosuppression with antithymocyte globulin, (methyl)prednisolone, and cyclosporin A is considered the treatment of choice for the patient with aplastic anemia without a donor for standard-risk stem cell transplantation. This consensus is supported by the results of several series, including a randomized German tria...
journal_title:Blood
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1182/blood-2002-04-1134
更新日期:2003-02-15 00:00:00
abstract::Plasma fibronectin enhances platelet thrombus formation on surfaces coated with collagen. We investigated the role of fibronectin assembly in this process. Platelets adherent to fibrillar type I collagen, but not platelets adherent to von Willebrand factor (VWF), supported assembly of plasma fibronectin under static c...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-02-002063
更新日期:2006-10-01 00:00:00
abstract::As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known cli...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-01-261396
更新日期:2010-06-10 00:00:00
abstract::The belief is widely held, on the basis of indirect evidence, that a substantial, even brief elevation of red cell Ca content must result in a marked shortening of circulatory survival. To test this notion directly, we exposed rabbit red cells in vitro to the ionophore A23187 and Ca so as to produce sustained uniform ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-07-01 00:00:00
abstract::Malignant cells are capable of influencing the microenvironment in a manner that facilitates tumor cell survival. Bidirectional crosstalk between chronic lymphocytic leukemic (CLL) cells and marrow-derived mesenchymal stromal cells (MSCs) activates both cell types. In this study, we observed that the conditioned mediu...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-02-269894
更新日期:2010-10-21 00:00:00
abstract::CD8alpha+ dendritic cells (DCs) represent a functionally distinct DC subset in vivo, which plays a critical role in initiating various cellular immune responses. However, the committed precursor of CD8alpha+ DCs remains to be identified. We reported here that murine splenic CD8alpha+CD11c- lineage phenotype (Lin)- cel...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v100.2.569
更新日期:2002-07-15 00:00:00
abstract::Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is initiated and driven by the oncogenic fusion protein BCR-ABL, a constitutively active tyrosine kinase. Despite major advances in the treatment of this highly aggressive disease with potent inhibitors of the BCR-ABL kinase such as dasatinib, pat...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2014-09-601062
更新日期:2015-02-26 00:00:00
abstract::We investigated whether atorvastatin (AT) was capable of protecting animals from acute graft-versus-host disease (aGVHD) across major histocompatibility complex (MHC) mismatch barriers. AT treatment of the donor induced a Th-2 cytokine profile in the adoptively transferred T cells and reduced their in vivo expansion, ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-08-106005
更新日期:2007-12-15 00:00:00
abstract::NF-kappaB is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-kappaB, could protect mice from lethal graft-versus-host disease (GVHD), which is charact...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-05-1820
更新日期:2006-01-15 00:00:00
abstract::Crystallographic structures indicate that gamma-chain residue Asn308 participates in D:D interactions and indeed substitutions of gammaAsn308 with lysine or isoleucine have been identified in dysfibrinogens with impaired polymerization. To probe the role of Asn308 in polymerization, we synthesized 3 variant fibrinogen...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-12-4296
更新日期:2004-06-01 00:00:00
abstract::The chemokine receptors (CCRs) CCR4 and CCR10, and the cutaneous lymphocyte antigen (CLA), have each been proposed as critical mediators of skin-specific TH lymphocyte homing in mice and humans. CLA initiates skin homing by mediating E-selectin-dependent tethering and rolling within cutaneous venules, but the specific...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-07-2348
更新日期:2003-03-01 00:00:00
abstract::Antigens implicated in the graft-versus-leukemia (GVL) effect in chronic myeloid leukemia (CML) include WT1, PR1, and BCR-ABL. To detect very low frequencies of these antigen-specific CD8+ T cells, we used quantitative polymerase chain reaction (qPCR) to measure interferon-gamma (IFN-gamma) mRNA production by peptide-...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-01-0150
更新日期:2003-10-15 00:00:00