Abstract:
:The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycolysis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.
journal_name
Haematologicajournal_title
Haematologicaauthors
Mendes RD,Canté-Barrett K,Pieters R,Meijerink JPdoi
10.3324/haematol.2016.146381subject
Has Abstractpub_date
2016-09-01 00:00:00pages
1010-7issue
9eissn
0390-6078issn
1592-8721pii
haematol.2016.146381journal_volume
101pub_type
杂志文章,评审相关文献
HAEMATOLOGICA文献大全abstract:BACKGROUND:Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. DESIGN AND METHODS:We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and anthracycline-based ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2011.044933
更新日期:2011-10-01 00:00:00
abstract::We investigated gastrointestinal graft-versus-host-disease using capsule endoscopy in patients with abdominal pain and/or diarrhea. We found severe pathology involving most of the gut including loss of villi, ulcerations, narrowing, bleeding and fistula formation. In 2 patients, capsule endoscopy alone established the...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2005-07-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Patients with aggressive non-Hodgkin's lymphomas (NHL) who do not obtain a complete response (CR) after induction chemotherapy have a poor prognosis. However, provided they are sensitive to the first regimen of chemotherapy, 25-40% of them with a B-cell phenotype may achieve long-term survival...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究
doi:
更新日期:2003-12-01 00:00:00
abstract::Reduction in minimal residual disease, measured by real-time quantitative PCR or flow cytometry, predicts prognosis in childhood B-cell precursor acute lymphoblastic leukemia. We explored whether cells reported as minimal residual disease by flow cytometry represent the malignant clone harboring clone-specific genomic...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2011.051383
更新日期:2012-01-01 00:00:00
abstract::Interactions between chronic lymphocytic leukemia (CLL) B cells and the bone marrow (BM) microenvironment play a major function in the physiopathology of CLL. Extracellular vesicles (EVs), which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about th...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2016.163337
更新日期:2017-09-01 00:00:00
abstract::The majority of responses produced in patients with low-grade lymphomas are unique among non-Hodgkin's lymphomas (NHL), and even with a more intensive chemotherapy regimen, they are only partial; the very few complete responses which are induced are usually of short duration and do not influence overall survival. Ther...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:1997-09-01 00:00:00
abstract::Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children's Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated ce...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2019.237230
更新日期:2021-01-01 00:00:00
abstract::Chronic graft-versus-host disease is a serious complication in long-term survivors of allogeneic hematopoietic stem cell transplantation, with several organ systems affected. Chronic graft-versus-host disease is an important cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. This a...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.13311
更新日期:2008-11-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Although several studies have reported on the use of children as donors for peripheral blood progenitor cells (PBPC), no specific characteristics have been identified as predictors of PBPC collection in this population. In this study we analyzed predictive factors for PBPC collection in pediat...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2003-08-01 00:00:00
abstract::High levels of HbF were found in patients with myelodysplastic syndrome (MDS), as well as a possible switching of the ratio of the gamma chains from the adult to the newborn type in 25% of our patients. These abnormalities in general were not present in the parents. The possibility of having thalassemia or other hemog...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1991-07-01 00:00:00
abstract:BACKGROUND:Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplanta...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2010.026682
更新日期:2010-12-01 00:00:00
abstract:BACKGROUND:Interleukin-17A is the signature cytokine of the Th17 subset and drives inflammatory pathology, but its relevance to autoantibody-mediated diseases is unclear. Th1 cells secreting interferon-γ have been implicated in autoimmune hemolytic anemia, so the aim was to determine which cytokine is more closely asso...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2011.060822
更新日期:2012-10-01 00:00:00
abstract::The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients w...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究
doi:10.3324/haematol.2014.109611
更新日期:2014-10-01 00:00:00
abstract::Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrop...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2016.151159
更新日期:2017-02-01 00:00:00
abstract:BACKGROUND:It has been shown that fludarabine (FLU) is superior to conventional treatment in B-CLL for rate and quality of response, leading to CR even at the molecular level. In this paper we report our preliminary results with this drug in B-CLL patients. METHODS AND PATIENTS:Twenty-seven B-CLL patients (16 refracto...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::Signaling through the αβT cell receptor (TCR) is a crucial determinant of T-cell fate and can induce two opposite outcomes during thymocyte development: cell death or survival and differentiation. To date, the role played by T-cell receptor in the oncogenic transformation of developing T cells remains unclear. Here we...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.188359
更新日期:2018-06-01 00:00:00
abstract::Relapsed/refractory multiple myeloma represents a major challenge in multiple myeloma therapy. For patients with relapsed/refractory multiple myeloma, we developed a treatment schema of metronomically scheduled drug therapy. We identified 186 patients who had been treated with metronomic therapy between March 2004 and...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2013.085183
更新日期:2013-07-01 00:00:00
abstract::The regulation of platelets by oxidants is critical for vascular health and may explain thrombotic complications in diseases such as diabetes and dementia, but remains poorly understood. Here, we describe a novel technique combining electron paramagnetic resonance spectroscopy and turbidimetry, which has been utilized...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.208819
更新日期:2019-09-01 00:00:00
abstract::To further clarify the role of ribosomal protein S14 (RPS14) in myelodysplastic syndrome, we examined RPS14 transcription in bone marrow derived CD34+ cells from patients with non-5q- myelodysplastic syndrome and found a reduced expression of RPS14 in 51 of 72 (71%) patients. MDS patients with an intermediate-1 risk (...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2009.008508
更新日期:2009-10-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Recent progress in the development of diagnostic techniques has greatly facilitated the monitoring of minimal residual disease (MRD) in patients with chronic myeloid leukemia (CML) after allogeneic bone marrow transplantation (BMT), the only curative treatment for this disease. The presence of...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:2000-10-01 00:00:00
abstract::Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression vi...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2019.239913
更新日期:2020-04-30 00:00:00
abstract:BACKGROUND:Imatinib can induce severe hepatotoxicity, in 1-5% of CML patients, many of whom need permanent imatinib discontinuation. DESIGN AND RESULTS:We report 5 CML patients who developed grade 3-4 hepatotoxicity after 2-8 months in imatinib. Different aetiologies of liver damage were ruled out and toxicity recurre...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2006-06-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Subgroups of T-cell acute lymphoblastic leukemia (T-ALL), defined according to recurrent cytogenetic aberrations, may have different prognoses. The aim of this study was to determine the prognostic relevance of molecular-cytogenetic abnormalities in pediatric patients using quantitative real-t...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2006-09-01 00:00:00
abstract::Circulating plasma thrombomodulin (TM) is an endothelial cell marker which may reflect endothelial injury. To find out to what extent diagnostic cardiac catheterization irritates vascular endothelium we conducted a prospective study in 91 children. Soluble TM concentrations, along with thrombin generation, were measur...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::The effect of treatment with 1,25-dihydroxyvitamin D3 administered at the dose of 1.50-3.00 ug/day for at least 12 months was evaluated in three patients with idiopathic myelofibrosis and in five patients with idiopathic thrombocythemia. This treatment did not cause any significant change in the hematological values o...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1990-05-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Patients with beta-thalassemia, like those with genetic hemochromatosis, develop iron overload due to increased iron absorption, and their iron burden is further exacerbated by transfusion therapy. Hepcidin, a hepatic hormone, regulates systemic iron homeostasis by inhibiting the absorption of...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.10842
更新日期:2007-05-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Recently, a chimeric monoclonal antibody (MoAb) directed against the CD20 antigen (rituximab) has been successfully introduced in the treatment of several CD20-positive B-cell neoplasias and particularly of follicular lymphomas. Based on these premises we evaluated the efficacy and the toxicit...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:
更新日期:2001-10-01 00:00:00
abstract::It is well known that thalassemic patients exhibit an increased frequency of thrombotic events. Most individuals with resistance to activated protein C (APCR) are the result of a point mutation replacing Arg 506 with Gln in the factor V aminoacidic sequence (factor V Leiden). Recently APCR has been shown to account fo...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1997-11-01 00:00:00
abstract::Macaques are emerging as a critical animal model in transfusion medicine, because of their evolutionary similarity to humans and perceived utility in discovery and translational science. However, little is known about the metabolism of Rhesus macaque red blood cells (RBC) and how this compares to human RBC metabolism ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2019.229930
更新日期:2020-08-01 00:00:00
abstract::Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patie...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2016.144428
更新日期:2016-07-01 00:00:00