Abstract:
:Effects of concurrent inhibition of mTORC1/2 and Bcl-2/Bcl-xL in human acute myeloid leukemia cells were examined. Tetracycline-inducible Bcl-2/Bcl-xL dual knockdown markedly sensitized acute myeloid leukemia cells to the dual TORC1/2 inhibitor INK128 in vitro as well as in vivo. Moreover, INK128 co-administered with the Bcl-2/xL antagonist ABT-737 sharply induced cell death in multiple acute myeloid leukemia cell lines, including TKI-resistant FLT3-ITD mutants and primary acute myeloid leukemia blasts carrying various genetic aberrations e.g., FLT3, IDH2, NPM1, and Kras, while exerting minimal toxicity toward normal hematopoietic CD34(+) cells. Combined treatment was particularly active against CD34(+)/CD38(-)/CD123(+) primitive leukemic progenitor cells. The INK128/ABT-737 regimen was also effective in the presence of a protective stromal microenvironment. Notably, INK128 was more potent than the TORC1 inhibitor rapamycin in down-regulating Mcl-1, diminishing AKT and 4EBP1 phosphorylation, and potentiating ABT-737 activity. Mcl-1 ectopic expression dramatically attenuated INK128/ABT-737 lethality, indicating an important functional role for Mcl-1 down-regulation in INK128/ABT-737 actions. Immunoprecipitation analysis revealed that combined treatment markedly diminished Bax, Bak, and Bim binding to all major anti-apoptotic Bcl-2 members (Bcl-2/Bcl-xL/Mcl-1), while Bax/Bak knockdown reduced cell death. Finally, INK128/ABT-737 co-administration sharply attenuated leukemia growth and significantly prolonged survival in a systemic acute myeloid leukemia xenograft model. Analysis of subcutaneous acute myeloid leukemia-derived tumors revealed significant decrease in 4EBP1 phosphorylation and Mcl-1 protein level, consistent with results obtained in vitro. These findings demonstrate that co-administration of dual mTORC1/mTORC2 inhibitors and BH3-mimetics exhibits potent anti-leukemic activity in vitro and in vivo, arguing that this strategy warrants attention in acute myeloid leukemia.
journal_name
Haematologicajournal_title
Haematologicaauthors
Rahmani M,Aust MM,Hawkins E,Parker RE,Ross M,Kmieciak M,Reshko LB,Rizzo KA,Dumur CI,Ferreira-Gonzalez A,Grant Sdoi
10.3324/haematol.2015.130351subject
Has Abstractpub_date
2015-12-01 00:00:00pages
1553-63issue
12eissn
0390-6078issn
1592-8721pii
haematol.2015.130351journal_volume
100pub_type
杂志文章相关文献
HAEMATOLOGICA文献大全abstract:BACKGROUND:Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25-40%. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem cell rescue. We report the results of a ...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:10.3324/haematol.2011.060434
更新日期:2012-11-01 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::Effects of angiotensin (Ang)-(1-7), an AngII metabolite, on bone marrow-derived hematopoietic cells were studied. We identified Ang-(1-7) to stimulate proliferation of human CD34(+) and mononuclear cells in vitro. Under in vivo conditions, we monitored proliferation and differentiation of human cord blood mononuclear ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2008.000034
更新日期:2009-06-01 00:00:00
abstract::Sixteen autologous stem cell transplant recipients received three vaccinations with conjugated haemophilus influenzae type b vaccine. Quantitative and qualitative aspects of the antibody response were studied. The vaccination schedule resulted in high antibody response rates and functional maturation of antibodies, as...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2005-11-01 00:00:00
abstract::Home care (HC) has an increasingly expanding role in the global management of patients affected by hematologic malignancies. Integrated strategies, including causal-targeted and supportive treatments according to hematologic expertise and a holistic approach inspired by the philosophy and practice of palliative medici...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:2006-11-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:A phase II study was conducted to investigate the effects of a therapeutic program based on the combination of fludarabine and cytarabine (ARA-C) administered as a sequential continuous infusion in untreated elderly patients with acute myeloid leukemia (AML). DESIGN AND METHODS:Sixty-three pa...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2005-06-01 00:00:00
abstract::Granulocyte colony-stimulating factor (G-CSF) can be administered after a peripheral blood stem cell transplantation with the aim of accelerating neutrophil recovery. In a randomized, single-blind study we studied a new administration schedule of G-CSF in this context. ...
journal_title:Haematologica
pub_type: 临床试验,信件,随机对照试验
doi:
更新日期:2004-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Acquired red cell aplasia (RCA) is a rare disorder and can be either idiopathic or associated with certain diseases, pregnancy, or drugs. In exceptionally rare cases, it has been reported to co-exist with other autoimmune cytopenias. We report a high incidence of RCA and autoimmune hemolytic a...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.10733
更新日期:2007-08-01 00:00:00
abstract::In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute l...
journal_title:Haematologica
pub_type: 临床试验,杂志文章,多中心研究
doi:10.3324/haematol.2013.085175
更新日期:2013-07-01 00:00:00
abstract::Interleukin-10 failed to modify either the percentage of bcl-2+ cells or the number of bcl-2 molecules, or to reduce 2-chlorodeoxyadenosine- and fludarabine-induced apoptosis. The cytokine at 0.1 ng/mL induced an increase of cell survival both in the absence or in the presence of 2-chlorodeoxyadenosine, while no diffe...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:1998-11-01 00:00:00
abstract::Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia (CML) and BCR-ABL1 inhibitor monotherapy fails to eliminate these cells, thereby necessitating alternate therapeutic strategies for patients CML. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone downr...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.194910
更新日期:2020-04-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Autologous stem cell transplantation (ASCT) is currently being evaluated as a therapy for patients with multiple sclerosis (MS). We report the results of a phase II trial to evaluate feasibility and toxicity of CD34+ selected ASCT (CD34+/ASCT) and treatment results at one year of follow-up. D...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:
更新日期:2003-03-01 00:00:00
abstract::Platelets are critical to arterial thrombosis, which underlies myocardial infarction and stroke. Activated platelets, regardless of the nature of their stimulus, initiate energy-intensive processes that sustain thrombus, while adapting to potential adversities of hypoxia and nutrient deprivation within the densely pac...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.205724
更新日期:2019-04-01 00:00:00
abstract::Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2014.115212
更新日期:2016-01-01 00:00:00
abstract::Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term adm...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2017.163675
更新日期:2017-10-01 00:00:00
abstract::We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with...
journal_title:Haematologica
pub_type: 临床试验,杂志文章,多中心研究
doi:10.3324/haematol.2013.086827
更新日期:2013-11-01 00:00:00
abstract:BACKGROUND:Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare th...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2009.019042
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:The diagnosis of myelodysplastic syndromes (MDS) is essentially morphological and based on the presence of dysplastic features in the peripheral blood and bone marrow. The French-American-British (FAB) Cooperative Group proposed a classification based on easily obtainable laboratory information...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:1998-03-01 00:00:00
abstract::We report on a case of acute myeloid leukemia in a 17-year old boy affected by Shwachman Diamond syndrome (SDS). Conventional cytogenetics at diagnosis revealed an abnormal clone with complex karyotypic changes including typical myeloid aberrations, such as monosomy 5, tetrasomy of chromosome 8, trisomy 9, and deletio...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:2000-11-01 00:00:00
abstract::Rituximab plus CHOP (R-CHOP) has been proven to increase overall survival in aggressive bcl-2-positive lymphoma patients. Using competing risk analysis, we studied the long-term impact of this treatment in patients from a GELA trial: R-CHOP prevented from progression or relapse in both bcl-2-positive and bcl-2-negativ...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2006-05-01 00:00:00
abstract::All hematopoietic cells that develop in the bone marrow must cross the endothelial barrier to enter the blood circulation. Blood platelets, however, are released by bigger protrusions of huge progenitor cells, named megakaryocytes, and enter the blood stream as so-called proplatelets before fragmenting into mature pla...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.202010
更新日期:2020-04-01 00:00:00
abstract::The development of inhibitors is currently one of the most serious complications in the treatment of hemophilic children. Prospective studies of previously untreated patients (PUP) showed that up to 52% of patients with severe hemophilia A developed inhibitors during the first 50 exposure days (ED) (>100 for outliers)...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:2003-06-01 00:00:00
abstract::Fibrinogen is an abundant protein synthesized in the liver, present in human blood plasma at concentrations ranging from 1.5-4 g/L in healthy individuals with a normal half-life of 3-5 days. With fibrin, produced by thrombin-mediated cleavage, fibrinogen plays important roles in many physiological processes. Indeed, t...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2019.236901
更新日期:2020-01-31 00:00:00
abstract::Juvenile hemochromatosis is a severe form of hereditary iron overload. It can be caused by mutations in either hepcidin or hemojuvelin genes. In this study we identified the molecular basis of juvenile hemochromatosis in three Australian families and assessed the role of potential modifying genes in individuals carryi...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2005-02-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Occult hepatitis B virus (HBV) infection might allow the release of viremic units into the blood supply network if blood is tested only for hepatitis B surface antigen (HBsAg). The aim of our study was to evaluate the actual prevalence, viral load and genotype of occult HBV infections among fi...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.11224
更新日期:2007-12-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Treatment of acute myeloid leukemia (AML) in older patients remains unsatisfactory. The BGMT 95 trial for older patients set out to improve the outcome of these patients by adding a third drug (lomustine) to a 5+7 idarubicin and cytarabine schedule at induction and evaluating intermediate-dose...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.3324/haematol.11068
更新日期:2007-10-01 00:00:00
abstract:BACKGROUND:The purpose of our cooperative trial was to investigate whether epirubicin (EPI) at 90 mg/m2 in a CHOP-like combination (called CEOP) could increase complete response (CR) and survival rates in non-Hodgkin lymphoma (NHL) patients while maintaining a tolerable degree of toxicity. METHODS:Between September 19...
journal_title:Haematologica
pub_type: 临床试验,杂志文章,多中心研究
doi:
更新日期:1995-07-01 00:00:00
abstract::Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.191601
更新日期:2018-08-01 00:00:00
abstract:BACKGROUND:In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied ...
journal_title:Haematologica
pub_type: 杂志文章,随机对照试验
doi:10.3324/haematol.2010.039131
更新日期:2011-08-01 00:00:00
abstract:BACKGROUND:In a study of childhood acute lymphoblastic leukemia (CoALL 06-97 study), the in vitro sensitivity of the patients' cells to prednisolone, vincristine and asparaginase was introduced as a new additional risk parameter for treatment stratification. In parallel in vivo treatment response was assessed by determ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2010.039735
更新日期:2011-06-01 00:00:00