Abstract:
:Most bone marrow (BM) malignancies develop in association with an angiogenic phenotype and increased numbers of endothelial cells. The molecular mechanisms involved in the modulation and recruitment of BM endothelium are largely unknown and may provide novel therapeutic targets for neoplastic diseases. We observed that angiogenic stimulation of BM endothelial cells activates mTOR and engages its downstream pathways 4E-BP1 and S6K1, which are inhibited by the mTOR-specific blockers rapamycin and CCI-779. Both mTOR blockers significantly inhibit growth factor- and leukemia-induced proliferation of BM endothelium by inducing G0/G1 cell-cycle arrest. This effect is associated with down-regulation of cyclin D1 and cdk2 phosphorylation, and up-regulation of the cdk inhibitors p27(kip1) and p21(cip1). Under conditions that reproduce the biomechanical fluidic environment of the BM, CCI-779 is equally effective in inhibiting BM endothelial-cell proliferation. Finally, simultaneous blockade of mTOR and NF-kappaB pathways synergize to significantly inhibit or abrogate the proliferative responses of BM endothelial cells to mitogenic stimuli. This study identifies mTOR as an important pathway for the proangiogenic stimulation of BM endothelium. Modulation of this pathway may serve as a valid therapeutic intervention in BM malignancies evolving in association with an angiogenic phenotype.
journal_name
Bloodjournal_title
Bloodauthors
Costa LF,Balcells M,Edelman ER,Nadler LM,Cardoso AAdoi
10.1182/blood-2005-06-2208subject
Has Abstractpub_date
2006-01-01 00:00:00pages
285-92issue
1eissn
0006-4971issn
1528-0020pii
2005-06-2208journal_volume
107pub_type
杂志文章相关文献
BLOOD文献大全abstract::Polymorphonuclear neutrophils (PMNs) have previously been reported to mediate phagocytosis of anti-CD20-opsonized B cells from patients with chronic lymphocytic leukemia (CLL). However, recent data have suggested that PMNs, like macrophages, can also mediate trogocytosis. We have performed experiments to more precisel...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-08-735605
更新日期:2017-05-11 00:00:00
abstract::Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive f...
journal_title:Blood
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1182/blood-2003-08-2644
更新日期:2004-02-15 00:00:00
abstract::The Leu-8 molecule, the human homologue of the murine MEL-14 peripheral lymph node homing receptor, is expressed on neutrophils in both species and may be important in localization of cells to sites of inflammation. Most circulating human neutrophils express the Leu-8 molecule, and activation of neutrophils with phorb...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1990-12-01 00:00:00
abstract::Interferons (IFNs) initiate their effects by interacting with specific high-affinity cell surface receptors, but little is known about the physiology of IFN receptor interaction in vivo. Treatment of patients suffering from hairy cell leukemia (HCL) with human recombinant alpha IFN results in significant tumor regress...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::Many B-lineage-specific genes are down-regulated in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We investigated the involvement of epigenetic modifications in gene silencing in cHL cell lines and in microdissected primary HRS cells. We assessed the expression and methylation status of C...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-09-3765
更新日期:2006-03-15 00:00:00
abstract::Gene expression patterns of CD34(+)CD38(-) cells derived from human embryonic stem cells (ESCs) were compared with those of cells isolated from adult human bone marrow (BM) using microarrays; 1692 and 1494 genes were expressed at levels at least 3-fold above background in cells from BM and ESCs, respectively. Of these...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-10-3575
更新日期:2004-06-01 00:00:00
abstract::Human mast cells in adult tissues have been thought to have limited, if any, proliferative potential. The current study examined mast cells obtained from adult skin and cultured in serum-free medium with recombinant human stem cell factor. During the first 4 weeks of culture, the percentages of mast cells increased fr...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.7.2045
更新日期:2001-04-01 00:00:00
abstract::Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein-mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These pa...
journal_title:Blood
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1182/blood-2002-11-3419
更新日期:2003-08-15 00:00:00
abstract::Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-06-724658
更新日期:2017-04-13 00:00:00
abstract::Despite many studies on the pathophysiology of antiphospholipid antibodies (aPL), the mechanism by which aPL causes thrombosis has not been established. We have tried to elucidate the paradox between the prolongation of the clotting time of phospholipid-dependent coagulation tests in vitro and the occurrence of thromb...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-05-15 00:00:00
abstract::The formation and functioning of the factor X activating complex on the surface of cultured human venous endothelial cells (HVEC) were investigated. To the HVEC monolayer human factors IXa, VIII, X, CaCl2, and S-2222 were added, and a gradually increasing activation of factor X was observed. The maximum activity of 88...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::The spatial distribution of subpopulations of hemopoietic progenitor cells following syngeneic transplantation was investigated at the single-cell level. The location of infused hemopoietic progenitor cells within the femoral bone marrow of nonablated recipients was determined by 5-(and-6)-carboxyfluorescein diacetate...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.8.2293
更新日期:2001-04-15 00:00:00
abstract::Six patients with relapsed hairy cell leukemia after splenectomy were treated with high-dose methotrexate and leucovorin rescue. Five patients had objective responses as determined by improved blood counts. In two of them, the response has continued for more than 14 and 44 months, respectively. Intensive treatment wit...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-07-01 00:00:00
abstract::Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the beta-globin complex on chromosome 11. Using microscopic radial imm...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-08-01 00:00:00
abstract::The biochemical basis for complement acting directly on antigen-presenting cells to enhance their function in T-cell stimulation has been unclear. Here we present evidence that engagement of C3a receptor (C3aR) on the surface of dendritic cells (DCs) leads to alterations in the level of intracellular cyclic adenosine ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2008-05-156646
更新日期:2008-12-15 00:00:00
abstract::Human transferrin receptor-2 (TFR-2) is a protein highly homologous to TFR-1/CD71 and is endowed with the ability to bind transferrin (TF) with low affinity. High levels of TFR-2 mRNA were found in the liver and in erythroid precursors. Mutations affecting the TFR-2 gene led to hemochromatosis type 3, a form of inheri...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-01-0076
更新日期:2002-11-15 00:00:00
abstract::Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein k...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2014-06-583518
更新日期:2015-01-08 00:00:00
abstract::Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown, and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biologic significance is unclear. We describe a new function of extracell...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-03-0918
更新日期:2003-03-01 00:00:00
abstract::Stem cell factor (SCF) binding to the c-kit receptor triggers homodimerization and intermolecular tyrosine phosphorylation of the c-kit receptor, thus initiating signal transduction. Receptor dimerization is a critical early step in this process. Prior biochemical studies of c-kit receptor dimerization have mainly use...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-02-01 00:00:00
abstract::Renal disease has not been considered a major late complication of bone marrow transplantation. Of 31 evaluable pediatric patients undergoing allogeneic or autologous bone marrow transplantation for neuroblastoma or acute lymphoblastic leukemia, 14 developed a hemolytic anemia, microscopic hematuria, and renal insuffi...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::Hematopoietic stem cells (HSCs) undergo dramatic expansion during fetal liver development, but attempts to expand their numbers ex vivo have failed. We hypothesized that unidentified fetal liver cells produce growth factors that support HSC proliferation. Here we describe a novel population of CD3+ and Ter119- day-15 ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-08-2955
更新日期:2004-04-01 00:00:00
abstract::The factor VIII/von Willebrand factor protein was radiolabeled after modification by galactose oxidase and reduction with tritiated potassium borohydride. This mild efficient method for labeling resulted in retention of over 90% of the biologic activities of the factor VIII/von Willebrand factor protein. Binding of th...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1980-01-01 00:00:00
abstract::Polycythemia vera (PV) treatment with interferon α (IFNα) is frequently limited by dose-related toxicity. PV CD34(+) cells are characterized by overexpression of Bcl-xL, which can be antagonized by ABT-737 leading to apoptosis. We explored the effects of ABT-737 and IFNα on PV hematopoiesis. Both IFNα and ABT-737 alon...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-04-279125
更新日期:2010-11-18 00:00:00
abstract::A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-05-089193
更新日期:2009-03-05 00:00:00
abstract::Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequenci...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-02-0642
更新日期:2005-09-15 00:00:00
abstract::Atypical hemolytic uremic syndrome (aHUS) is associated with complement system dysregulation, and more than 25% of pediatric aHUS cases are linked to mutations in complement factor H (CFH) or CFH autoantibodies. The observation of thrombocytopenia and platelet-rich thrombi in the glomerular microvasculature indicates ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-03-205096
更新日期:2009-11-12 00:00:00
abstract::Phosphatidylserine (PS) is normally confined to the cytoplasmic leaflet of the red blood cell (RBC) membrane, but some sickle RBCs expose PS in the outer leaflet (PS+ cells). This study examined the relationships among PS externalization, fetal hemoglobin content, hydration state, and cell age. Sickle RBCs exhibit a w...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-11-3416
更新日期:2003-07-01 00:00:00
abstract::HGAL is a newly identified germinal center (GC)-specific gene whose expression by the tumor cells correlates with a favorable prognosis in patients with diffuse large B-cell and classical Hodgkin lymphomas. The function of HGAL is unknown. Previous studies demonstrated that HGAL is dispensable for GC formation, immuno...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-04-087775
更新日期:2007-12-15 00:00:00
abstract::Chronic lymphocytic leukemia of B-cell origin (B-CLL) is generally thought to arise by neoplastic transformation of B lymphocytes, which express CD5 and have features of an early stage of B-cell differentiation. To study isotype-switched B-CLL as a potentially more differentiated variant, we performed genetic and func...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-11-01 00:00:00
abstract::Sickle cell anemia (SCA) is an inherited disorder of beta-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.12.3960
更新日期:2001-06-15 00:00:00