Abstract:
:Folylpoly-gamma-gluatamate synthetase (FPGS) catalyzes the polyglutamylation and thus intracellular retention of folates and antifolates (eg, methotrexate; MTX) through the addition of multiple glutamate equivalents to their gamma-carboxyl residue. Since polyglutamylation of antifolates is crucial for their pharmacological activity in leukemia, loss of FPGS function results in decreased cellular levels of polyglutamylation-dependent antifolates and consequent drug resistance. Whereas resistance to pulse exposure to antifolates is frequently associated with loss of FPGS activity, the underlying molecular mechanism remains elusive. Here we explored the molecular basis of antifolate resistance in human MTX-resistant leukemia cell lines displaying marked loss of FPGS activity. We demonstrate that these MTX-resistant cells exhibit impaired splicing of FPGS mRNA based on intron retention and/or exon skipping, thereby resulting in loss of FPGS function due to premature translation termination. Furthermore, analysis of FPGS transcripts in blood or bone marrow specimens from patients with acute lymphoblastic leukemia revealed exon 12 skipping, both at diagnosis and at relapse, the latter of which occurs after high-dose MTX-containing chemotherapy. These results constitute the first demonstration of the loss of FPGS function via aberrant mRNA splicing, thereby resulting in loss of antifolate retention and drug resistance. The clinical ramifications of these novel findings are discussed.
journal_name
Bloodjournal_title
Bloodauthors
Stark M,Wichman C,Avivi I,Assaraf YGdoi
10.1182/blood-2008-08-173799subject
Has Abstractpub_date
2009-04-30 00:00:00pages
4362-9issue
18eissn
0006-4971issn
1528-0020pii
blood-2008-08-173799journal_volume
113pub_type
杂志文章相关文献
BLOOD文献大全abstract::Mast cells accumulate at sites of neovascularization, solid tumors, and many immune reactions. Such accumulation requires directed migration of mature mast cells or their precursors. The nature of the chemoattractants that regulate mast cell motility and the identity of the receptors that mediate the chemotactic respo...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-02-15 00:00:00
abstract::Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors hav...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-06-358374
更新日期:2012-02-16 00:00:00
abstract::Hand mirror cells are a morphological configuration that are seen in immunologically stimulated lymphocytes and can be induced by antigen--antibody complexes. Therefore, the bone marrow and peripheral blood plasma of two patients with acute lymphoblastic leukemia--hand mirror variant were evaluated for the presence of...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1980-10-01 00:00:00
abstract::Regulatory T (Tr) cells have the potential to treat immune-mediated disease, but cloning such cells for study from patients with autoimmune disease has proven difficult. Here, we describe autoantigen-specific, interleukin-10 (IL-10)-secreting Tr cell clones recovered ex vivo from a patient with autoimmune hemolytic an...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-07-101345
更新日期:2008-01-15 00:00:00
abstract::Despite matching for serologically defined HLA-A, B, DR antigens, acute graft-versus-host disease (GVHD) is a major complication contributing to increased morbidity and mortality in patients who undergo marrow transplantation from unrelated donors. The extent to which unrecognized mismatching for alleles that encode D...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1995-08-15 00:00:00
abstract::Expression of the von Willebrand factor (vWF) gene is restricted to the endothelial and megakaryocyte lineages. Within the endothelium, expression of vWF varies between different vascular beds. We have previously shown that the human vWF promoter spanning a region between -2182 (relative to the start site of transcrip...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-11-15 00:00:00
abstract::Fetal hemoglobin (HbF) and adult hemoglobin (HbA) synthesis was studied in fetal baboons, Papio cynocephalus, to determine the normal pattern of hemoglobin production during fetal development. Fetuses ranging from 53 to 180 days gestation (term gestation 184 days) were used. Erythroid cells were incubated with 3H-L-le...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1979-01-01 00:00:00
abstract::Without a prior history of hemorrhagic disease, a 62-year-old man suffered recurrent episodes of bleeding. Solubility of the patient's clot in 5 mol/L urea indicated a problem with fibrin stabilization. The transamidase activity potential of factor XIII, measured by the incorporation of radioactive putrescine into N,N...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-02-01 00:00:00
abstract::Enhanced tolerance to combination chemotherapy has been cited as an ancillary benefit of staging laparotomy and splenectomy in Hodgkin's disease. Seventeen patients with Hodgkin's disease and 15 with non-Hodgkin's lymphoma were subjected to nontherapeutic splenectomy as part of the staging procedure prior to their ini...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1976-02-01 00:00:00
abstract::Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis ...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2009-08-236596
更新日期:2010-04-08 00:00:00
abstract::Antisense oligodeoxynucleotide (ODN) drugs might be more effective if their delivery was optimized and they were targeted to short-lived proteins encoded by messenger RNA (mRNA) species with equally short half-lives. To test this hypothesis, an ODN targeted to the c-myb proto-oncogene was developed and used to purge m...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood.v99.4.1150
更新日期:2002-02-15 00:00:00
abstract::The Epstein-Barr virus (EBV) is known to cause posttransplant lymphoproliferative disease (PTLD) in immunosuppressed transplant patients. The results of this pilot study showed that all EBV- patients pretransplant experienced primary EBV infection within the first 3 months after transplant surgery. Virtually all of th...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute ...
journal_title:Blood
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1182/blood.2019004114
更新日期:2020-04-16 00:00:00
abstract::This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patie...
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:1995-07-15 00:00:00
abstract::Hyperresponsiveness to growth factors underlies a wide variety of human diseases,including hemangiomas, the most common tumor of childhood. Hemangiomas have been found to be clonal neoplasms of endothelial cells, with somatic mutations in unknown genes likely to be responsible for their development. ...
journal_title:Blood
pub_type: 评论,杂志文章
doi:10.1182/blood-2012-04-415059
更新日期:2012-05-17 00:00:00
abstract::One hundred forty-two patients between the ages of 1 and 17 years who survived disease-free more than 1 year after marrow transplantation for hematologic malignancy had growth and development evaluations from one to 14 years posttransplant (median 4 years). Prior to transplant all children received multiagent chemothe...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::Self-renewal is a feature of cancer and can be assessed by cell transplantation into immune-compromised or immune-matched animals. However, studies in zebrafish have been severely limited by lack of these reagents. Here, Myc-induced T-cell acute lymphoblastic leukemias (T-ALLs) have been made in syngeneic, clonal zebr...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-10-246488
更新日期:2010-04-22 00:00:00
abstract::The effect of cyclosporine A (CyA) on the ability of the human immunodeficiency virus type 1 (HIV-1) to infect the H-9 T-cell leukemic line, as well as interleukin-2 (IL-2)-grown human peripheral blood-derived lymphocytes, has been studied. Pretreatment of H-9 cells and human lymphocytes with CyA over 24 hours complet...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::In this issue of Blood, Goussetis et al identify autophagy as a new pathway for the degradation of the oncoprotein BCR-ABL. They show that the therapeutic drug arsenic trioxide (AS(2)O(3)) targets BCR-ABL for autophagic degradation via a p62/SQSTM1-dependent mechanism that is critical for the antileukemic effect of th...
journal_title:Blood
pub_type: 评论,杂志文章
doi:10.1182/blood-2012-08-451492
更新日期:2012-10-25 00:00:00
abstract::Bax is a proapoptotic member of the Bcl-2 protein family. The incidence and prognostic significance of Bax protein expression in diffuse non-Hodgkin's lymphomas with a large cell component (DLCL) was determined by an immunohistochemical method by using paraffin-embedded tumors from a cohort of patients treated uniform...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-10-15 00:00:00
abstract::We have studied adenovirus-mediated cytotoxicity after infection of malignant cells obtained from patients with chronic lymphocytic leukemia (CLL). Our studies indicate that adenoviruses can infect primary CLL cells and that infection of CLL cells with a replication-competent strain of human adenovirus 5 (Ad5dl309) re...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-11-15 00:00:00
abstract::We have identified a small molecular weight compound, SCH 14988, which specifically stimulates in vitro granulocyte-colony stimulating factor (G-CSF) production from activated human peripheral blood mononuclear cells and monocytes but not other cytokines or CSFs with hematoregulatory activity. In vivo administration o...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-07-15 00:00:00
abstract::An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion-binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody wa...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-09-15 00:00:00
abstract::Monoclonally-derived neoplastic T-cells from a patient with cutaneous T-cell lymphoma respond to multiple human HLA-D antigens in mixed lymphocyte culture. The implications of this phenomenon relevant to normal T-cell function and to malignancy are discussed. ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1980-03-01 00:00:00
abstract::The CD28 family of receptors (CD28, cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], inducible costimulator [ICOS], program death-1 [PD-1], and B- and T-lymphocyte attenuator [BTLA]) plays a critical role in controlling the adaptive arm of the immune response. While considerable information is available regarding...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2004-04-1596
更新日期:2005-01-01 00:00:00
abstract::We have developed a new helper-dependent (HD) adenoviral vector FTC that contains 3 cis-acting sequences as stuffer DNA: a human fragment of alphoid repeat DNA, matrix-attachment regions (MARs), and the hepatocyte control region enhancer. To determine the most robust human coagulation factor IX (hFIX) expression casse...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v99.11.3923
更新日期:2002-06-01 00:00:00
abstract::Mutations in the SH2D1A gene have been described in most patients with the clinical syndrome of X-linked lymphoproliferative disease (XLP). The diagnosis of XLP is still difficult given its clinical heterogeneity and the lack of a readily available rapid diagnostic laboratory test, particularly in patients without a f...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood-2004-09-3651
更新日期:2005-04-15 00:00:00
abstract::This study examines the role of neutrophils (PMN) in the pathogenesis of endotoxin-induced microclot formation. It is intended to clarify whether granulocytes are involved in endotoxin-induced activation of intravascular coagulation (generation of soluble fibrin) and/or in endotoxin-induced precipitation of soluble fi...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1975-05-01 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::Using a polyclonal antiserum against canine CD34, we previously found that CD34 is expressed on canine bone marrow progenitor cells in a manner analogous to that found in humans. To further characterize CD34+ cells and to facilitate preclinical canine stem cell transplant studies, monoclonal antibodies (MoAbs) were ra...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-03-15 00:00:00