Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies.

Abstract:

:The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.

journal_name

Blood

journal_title

Blood

authors

Gupta M,Hendrickson AE,Yun SS,Han JJ,Schneider PA,Koh BD,Stenson MJ,Wellik LE,Shing JC,Peterson KL,Flatten KS,Hess AD,Smith BD,Karp JE,Barr S,Witzig TE,Kaufmann SH

doi

10.1182/blood-2011-04-346601

subject

Has Abstract

pub_date

2012-01-12 00:00:00

pages

476-87

issue

2

eissn

0006-4971

issn

1528-0020

pii

blood-2011-04-346601

journal_volume

119

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia.

    abstract::Pure red cell aplasia (PRCA) is a rare complication in patients with chronic lymphocytic leukemia (CLL). It is characterized by reticulocytopenia and by an absence of red cell precursors in the bone marrow. Unlike autoimmune hemolytic anemia, which is characterized by an increased number of reticulocytes, positive Coo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v99.3.1092

    authors: Ghazal H

    更新日期:2002-02-01 00:00:00

  • Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion.

    abstract::Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose p...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-08-523001

    authors: Bachireddy P,Hainz U,Rooney M,Pozdnyakova O,Aldridge J,Zhang W,Liao X,Hodi FS,O'Connell K,Haining WN,Goldstein NR,Canning CM,Soiffer RJ,Ritz J,Hacohen N,Alyea EP 3rd,Kim HT,Wu CJ

    更新日期:2014-02-27 00:00:00

  • Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes.

    abstract::The role of T-cell subsets in the induction of tissue factor (TF) production by human monocytes in vitro was investigated. Mitogen stimulation enabled both unfractionated T cells and their CD4+ or CD8+ subsets to promote procoagulant activity (PCA). After mitogen or antigen activation, all seven T-cell clones with Th1...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Del Prete G,De Carli M,Lammel RM,D'Elios MM,Daniel KC,Giusti B,Abbate R,Romagnani S

    更新日期:1995-07-01 00:00:00

  • Manipulating leukocyte interactions in vivo through optogenetic chemokine release.

    abstract::Light-mediated release of signaling ligands, such as chemoattractants, growth factors, and cytokines is an attractive strategy for investigation and therapeutic targeting of leukocyte communication and immune responses. We introduce a versatile optogenetic method to control ligand secretion, combining UV-conditioned e...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2015-11-684852

    authors: Sarris M,Olekhnovitch R,Bousso P

    更新日期:2016-06-09 00:00:00

  • The role of calcium in lymphocyte proliferation. (An interpretive review).

    abstract::A small quantity of extracellular calcium is required for the stimulation of lymphocytes by mitogens such as plant lectins. Lectin binding to the lymphocyte surface and early postbinding events that eventually lead to DNA synthesis are calcium dependent. Mitogenic lectins such as PHA and Con-A rapidly increase the siz...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:

    authors: Lichtman AH,Segel GB,Lichtman MA

    更新日期:1983-03-01 00:00:00

  • Amelioration of Sardinian beta0 thalassemia by genetic modifiers.

    abstract::Sardinian beta-thalassemia patients all are homozygotes for the same null allele in the beta-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of alpha-thalassemia or the presence of genetic variants that sustain fetal hemoglobin product...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2009-04-217901

    authors: Galanello R,Sanna S,Perseu L,Sollaino MC,Satta S,Lai ME,Barella S,Uda M,Usala G,Abecasis GR,Cao A

    更新日期:2009-10-29 00:00:00

  • Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production.

    abstract::We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-01-0012

    authors: Kim MR,Manoukian R,Yeh R,Silbiger SM,Danilenko DM,Scully S,Sun J,DeRose ML,Stolina M,Chang D,Van GY,Clarkin K,Nguyen HQ,Yu YB,Jing S,Senaldi G,Elliott G,Medlock ES

    更新日期:2002-10-01 00:00:00

  • Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications, is an inherited disorder.

    abstract::An as yet single family with a bleeding history is shown to present the characteristic lack of membrane expression of procoagulant phospholipids observed in Scott syndrome. Low prothrombin consumption in the serum of the propositus, a 71-year-old woman, and two of her children was the sole abnormal hemostasis paramete...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Toti F,Satta N,Fressinaud E,Meyer D,Freyssinet JM

    更新日期:1996-02-15 00:00:00

  • RANK ligand and osteoprotegerin in myeloma bone disease.

    abstract::Myeloma bone disease is due to interactions of myeloma cells with the bone marrow microenvironment, and is associated with pathologic fractures, neurologic symptoms and hypercalcemia. Adjacent to myeloma cells, the formation and activation of osteoclasts is increased, which results in enhanced bone resorption. The rec...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2002-09-2684

    authors: Sezer O,Heider U,Zavrski I,Kühne CA,Hofbauer LC

    更新日期:2003-03-15 00:00:00

  • Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization.

    abstract::Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are pro...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2012-07-441527

    authors: Gaál EI,Tammela T,Anisimov A,Marbacher S,Honkanen P,Zarkada G,Leppänen VM,Tatlisumak T,Hernesniemi J,Niemelä M,Alitalo K

    更新日期:2013-08-01 00:00:00

  • Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2.

    abstract::The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter contains a consensus sequence for the polyomavirus enhancer binding-protein 2 (PEBP2) transcription factor, which consists of alpha and beta subunits. There are at least two genes, alpha A and alpha B, encoding the alpha subunit. alpha B is th...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Takahashi A,Satake M,Yamaguchi-Iwai Y,Bae SC,Lu J,Maruyama M,Zhang YW,Oka H,Arai N,Arai K

    更新日期:1995-07-15 00:00:00

  • Interleukin 2-activated killer cells in patients following transplants of soybean lectin-separated and E rosette-depleted bone marrow.

    abstract::During the early period following bone marrow transplantation before the immune system has reached full functional maturity, unprimed, nonspecific lytic systems may play a critical role as antiviral or antitumor effectors. The reconstitution of cells with this potential is of particular importance in recipients of bon...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Keever CA,Welte K,Small T,Levick J,Sullivan M,Hauch M,Evans RL,O'Reilly RJ

    更新日期:1987-12-01 00:00:00

  • Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis.

    abstract::p27 is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G(1)/S progression, and whose activity is, in part, regulated through interactions with D-type cyclins. Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation resulting in deregulated cyclin D1. We previously showed ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-01-0263

    authors: Quintanilla-Martinez L,Davies-Hill T,Fend F,Calzada-Wack J,Sorbara L,Campo E,Jaffe ES,Raffeld M

    更新日期:2003-04-15 00:00:00

  • Glycoprotein Ib (GPIb)-dependent and GPIb-independent pathways of thrombin-induced platelet activation.

    abstract::In this study, the question of whether glycoprotein Ib (GPIb) mediates both high and moderate affinity pathways of alpha-thrombin-induced platelet activation was examined. Flow cytometric studies, using a panel of monoclonal antibodies (MoAbs), showed that Serratia marcescens protease treatment removed greater than 97...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Yamamoto N,Greco NJ,Barnard MR,Tanoue K,Yamazaki H,Jamieson GA,Michelson AD

    更新日期:1991-04-15 00:00:00

  • EZH2 mutational status predicts poor survival in myelofibrosis.

    abstract::We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were de...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2011-06-363424

    authors: Guglielmelli P,Biamonte F,Score J,Hidalgo-Curtis C,Cervantes F,Maffioli M,Fanelli T,Ernst T,Winkelman N,Jones AV,Zoi K,Reiter A,Duncombe A,Villani L,Bosi A,Barosi G,Cross NC,Vannucchi AM

    更新日期:2011-11-10 00:00:00

  • Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation.

    abstract::Cutaneous T-cell lymphomas (CTCLs) primarily affect skin and are characterized by proliferation of mature CD4(+) T-helper cells. The pattern of cytokine production in the skin and blood is considered to be of major importance for the pathogenesis of CTCLs. Abnormal cytokine expression in CTCLs may be responsible for e...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-07-590398

    authors: Geskin LJ,Viragova S,Stolz DB,Fuschiotti P

    更新日期:2015-04-30 00:00:00

  • Thalidomide as salvage therapy for chronic graft-versus-host disease.

    abstract::Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixt...

    journal_title:Blood

    pub_type: 临床试验,杂志文章,多中心研究

    doi:

    authors: Parker PM,Chao N,Nademanee A,O'Donnell MR,Schmidt GM,Snyder DS,Stein AS,Smith EP,Molina A,Stepan DE,Kashyap A,Planas I,Spielberger R,Somlo G,Margolin K,Zwingenberger K,Wilsman K,Negrin RS,Long GD,Niland JC,Blume K

    更新日期:1995-11-01 00:00:00

  • A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.

    abstract::The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response have never been validated. Newly diagnosed patients from the Pavia (n = 461, testing cohort) and Heidelberg (n = 271, val...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-04-570010

    authors: Palladini G,Hegenbart U,Milani P,Kimmich C,Foli A,Ho AD,Vidus Rosin M,Albertini R,Moratti R,Merlini G,Schönland S

    更新日期:2014-10-09 00:00:00

  • Enhanced engraftment of hematopoietic progenitor cells in mice treated with granulocyte colony-stimulating factor before low-dose irradiation: implications for gene therapy.

    abstract::Gene therapy for inherited disorders of blood cells will require both efficient methods for stable gene transfer and nonablative bone marrow conditioning regimens to allow engraftment of modified hematopoietic progenitor cells (HPCs). We have used a sensitive murine system for detecting HPC engraftment using congenic ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Mardiney M 3rd,Malech HL

    更新日期:1996-05-15 00:00:00

  • The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors.

    abstract::The monoclonal antibody STRO-1 identifies clonogenic bone marrow stromal cell progenitors (fibroblast colony-forming units [CFU-F]) in adult human bone marrow. These STRO-1+ CFU-F have previously been shown to give rise to cells with the phenotype of fibroblasts, adipocytes, and smooth muscle cells. In this study, the...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Gronthos S,Graves SE,Ohta S,Simmons PJ

    更新日期:1994-12-15 00:00:00

  • Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor.

    abstract::The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ p...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-03-0891

    authors: Stebbing J,Gazzard B,Portsmouth S,Gotch F,Kim L,Bower M,Mandalia S,Binder R,Srivastava P,Patterson S

    更新日期:2003-09-01 00:00:00

  • Demonstration and mode of action of an inhibitor for activated Hageman factor (factor XIIa) of the intrinsic blood coagulation pathway from Schistosoma mansoni.

    abstract::An anticoagulant activity from adult Schistosoma mansoni whole worm homogenate is described. The inhibitor appears to be specific for the contact activation step of the intrinsic pathway. Experiments with both human and mouse plasmas have defined the specificity of the inhibitor as follows: (1) It lengthens the partia...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Tsang VC,Damian RT

    更新日期:1977-04-01 00:00:00

  • Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features.

    abstract::The spread of multiple myeloma (MM) involves (re)circulation into the peripheral blood and (re)entrance or homing of MM cells into new sites of the BM. Hypoxia in solid tumors was shown to promote metastasis through activation of proteins involved in the epithelial-mesenchymal transition (EMT) process. We hypothesized...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2011-09-380410

    authors: Azab AK,Hu J,Quang P,Azab F,Pitsillides C,Awwad R,Thompson B,Maiso P,Sun JD,Hart CP,Roccaro AM,Sacco A,Ngo HT,Lin CP,Kung AL,Carrasco RD,Vanderkerken K,Ghobrial IM

    更新日期:2012-06-14 00:00:00

  • Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes.

    abstract::Macrophage colony-stimulating factor (M-CSF or CSF-1) and granulocyte-macrophage CSF (GM-CSF) have been shown to increase human monocyte urokinase-type plasminogen-activator (u-PA) activity with possible consequences for cell migration and tissue remodeling; because monocyte u-PA activity is likely to be controlled in...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hamilton JA,Whitty GA,Stanton H,Wojta J,Gallichio M,McGrath K,Ianches G

    更新日期:1993-12-15 00:00:00

  • Hemophilia B Leyden: substitution of thymine for guanine at position -21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter.

    abstract::Hemophilia B Leyden is an X chromosome-linked bleeding disorder characterized by an altered developmental expression of blood coagulation factor IX. This form of hemophilia B has been found to be associated with a variety of single point mutations in the factor IX promoter region. We now describe a novel point mutatio...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Reijnen MJ,Peerlinck K,Maasdam D,Bertina RM,Reitsma PH

    更新日期:1993-07-01 00:00:00

  • Selection of patients for bone marrow transplantation in severe aplastic anemia.

    abstract::Despite androgens and intensive supportive care, satisfactory survival in severe aplastic anemia remains at 20% or less. Histocompatible bone marrow transplantation can restore normal hematopoiesis in approximately 40% of similarly severe individuals. Delay of transplantation for 3 wk after diagnosis allows time for p...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Camitta BM,Rappeport JM,Parkman R,Nathan DG

    更新日期:1975-03-01 00:00:00

  • ALK+ lymphoma: clinico-pathological findings and outcome.

    abstract::A distinct pathologic entity (ALK+ lymphoma) that is characterized by expression of the anaplastic lymphoma kinase (ALK) protein has recently emerged within the heterogeneous group of CD30(+) anaplastic large-cell lymphomas. Information on clinical findings and treatment outcome of ALK+ lymphoma is still limited, and ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Falini B,Pileri S,Zinzani PL,Carbone A,Zagonel V,Wolf-Peeters C,Verhoef G,Menestrina F,Todeschini G,Paulli M,Lazzarino M,Giardini R,Aiello A,Foss HD,Araujo I,Fizzotti M,Pelicci PG,Flenghi L,Martelli MF,Santucci A

    更新日期:1999-04-15 00:00:00

  • Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma.

    abstract::In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-02-268003

    authors: Richter-Larrea JA,Robles EF,Fresquet V,Beltran E,Rullan AJ,Agirre X,Calasanz MJ,Panizo C,Richter JA,Hernandez JM,Roman-Gomez J,Prosper F,Martinez-Climent JA

    更新日期:2010-10-07 00:00:00

  • Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis.

    abstract::Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207(+) dendritic cells with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-05-577825

    authors: Chakraborty R,Hampton OA,Shen X,Simko SJ,Shih A,Abhyankar H,Lim KP,Covington KR,Trevino L,Dewal N,Muzny DM,Doddapaneni H,Hu J,Wang L,Lupo PJ,Hicks MJ,Bonilla DL,Dwyer KC,Berres ML,Poulikakos PI,Merad M,McClain K

    更新日期:2014-11-06 00:00:00

  • Chronic lymphocytic leukemia and the Warburg effect.

    abstract::In this issue of Blood, Jitschin et al demonstrate a microenvironmental glycolytic shift in chronic lymphocytic leukemia (CLL) cells mediated by Notch-c-Myc signaling. Interfering in the Notch-c-Myc pathway and reprogramming glycolytic metabolism could contribute to overcoming drug resistance in CLL. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2015-04-636332

    authors: Moreno C

    更新日期:2015-05-28 00:00:00