Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia.

Abstract:

:Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in chronic lymphocytic leukemia cells by inhibiting Cdk7 and Cdk9, which control transcription. Here we studied the novel Cdk inhibitor SNS-032, which exhibits potent and selective inhibitory activity against Cdk2, Cdk7, and Cdk9. We hypothesized that transient inhibition of transcription by SNS-032 would decrease antiapoptotic proteins, resulting in cell death. SNS-032 effectively killed chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. This was associated with inhibition of phosphorylation of RNA polymerase II and inhibition of RNA synthesis. Consistent with the intrinsic turnover rates of their transcripts and proteins, antiapoptotic proteins, such as Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), were rapidly reduced on exposure to SNS-032, whereas Bcl-2 protein was not affected. The initial decrease of Mcl-1 protein was the result of transcriptional inhibition rather than cleavage by caspase. Compared with flavopiridol and roscovitine, SNS-032 was more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity was readily reversible; removal of SNS-032 reactivated RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. Thus, these data support the clinical development of SNS-032 in diseases that require short-lived oncoproteins for survival.

journal_name

Blood

journal_title

Blood

authors

Chen R,Wierda WG,Chubb S,Hawtin RE,Fox JA,Keating MJ,Gandhi V,Plunkett W

doi

10.1182/blood-2008-12-190256

subject

Has Abstract

pub_date

2009-05-07 00:00:00

pages

4637-45

issue

19

eissn

0006-4971

issn

1528-0020

pii

blood-2008-12-190256

journal_volume

113

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load.

    abstract::The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between so...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Aarts WM,Bende RJ,Steenbergen EJ,Kluin PM,Ooms EC,Pals ST,van Noesel CJ

    更新日期:2000-05-01 00:00:00

  • Gene therapy. Factor IX Padua: them that have, give.

    abstract::In this issue of Blood, Finn et al have taken a factor IX variant with increased specific activity associated with thrombophilia and used it to improve gene therapy of hemophilia B in dogs, and Cantore et al have shown similar results in mice. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2012-09-452821

    authors: Lozier JN

    更新日期:2012-11-29 00:00:00

  • Acquired granular pool defect in stored platelets.

    abstract::Platelets stored as concentrates (PC) for 72 h at 22 degrees C develop a functional defect. Alterations in adenine nucleotides of platelets have been shown to affect platelet function. Adenine nucleotide content of platelets was measured before and after storage and a decrease of 27.1 /+- 1.7% (mean /+- SE) in ATP and...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Rao AK,Niewiarowski S,Murphy S

    更新日期:1981-02-01 00:00:00

  • Fetal erythropoiesis in juvenile chronic myelocytic leukemia.

    abstract::Red cell enzymes, 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP), were evaluated in a 23-mo-old boy with juvenile chronic myelocytic leukemia (JCML) at the onset of his illness and 6 mo later during the accelerated phase. The activities of the age-dependent red cell enzymes, hexokinase, aldolase, py...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Travis SF

    更新日期:1983-09-01 00:00:00

  • Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections.

    abstract::We found an unusual fc gamma receptor IIIa (CD16) phenotype on the natural killer (NK) cells of a 3-year-old boy, who suffered from recurrent viral respiratory tract infections since birth. He also had severe clinical problems after Bacille Calmette-Geérin (BCG) vaccination and following Epstein-Barr virus and Varicel...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: de Vries E,Koene HR,Vossen JM,Gratama JW,von dem Borne AE,Waaijer JL,Haraldsson A,de Haas M,van Tol MJ

    更新日期:1996-10-15 00:00:00

  • Tumor vascular targeting therapy with viral vectors.

    abstract::Tumor angiogenesis is crucial for the progression and metastasis of cancer. The vasculature of tumor tissue is different from normal vasculature. Therefore, tumor vascular targeting therapy could represent an effective therapeutic strategy with which to suppress both primary tumor growth and tumor metastasis. The use ...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2005-10-4114

    authors: Liu Y,Deisseroth A

    更新日期:2006-04-15 00:00:00

  • On the target specificity of plasminogen activator inhibitor 1: the role of heparin, vitronectin, and the reactive site.

    abstract::Plasminogen activator inhibitor 1 (PAI-1) is the fast-acting inhibitor of both tissue-type and urokinase-type plasminogen activators (t-PA, u-PA) and is an essential regulatory protein of the fibrinolytic system. In the presence of either the protein vitronectin or the glycosaminoglycan heparin, PAI-1 is also an effic...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Keijer J,Linders M,Wegman JJ,Ehrlich HJ,Mertens K,Pannekoek H

    更新日期:1991-09-01 00:00:00

  • Liposomal ET-18-OCH(3) induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling.

    abstract::ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH(3)), is a nonmyelosuppressive antiproliferative agent that is more effective and less toxic than the ether lipid itself in tumor model systems. We found that ELL-12 induced apoptosis in Jurkat, H9, and U-9...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Cuvillier O,Mayhew E,Janoff AS,Spiegel S

    更新日期:1999-11-15 00:00:00

  • Role of transforming growth factor-beta in hematologic malignancies.

    abstract::The transforming growth factor-beta (TGF-beta) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-beta signaling pathway is a potent negative regulator of proliferation while stimulating differentiatio...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2005-10-4169

    authors: Dong M,Blobe GC

    更新日期:2006-06-15 00:00:00

  • All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol.

    abstract::We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is rep...

    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:10.1182/blood-2002-02-0632

    authors: Tallman MS,Andersen JW,Schiffer CA,Appelbaum FR,Feusner JH,Woods WG,Ogden A,Weinstein H,Shepherd L,Willman C,Bloomfield CD,Rowe JM,Wiernik PH

    更新日期:2002-12-15 00:00:00

  • Hematopoietic stem cell transplantation for de novo erythroleukemia: a study of the European Group for Blood and Marrow Transplantation (EBMT).

    abstract::De novo erythroleukemia (EL) is a rare disease. Reported median survival are poor and vary from 4 to 14 months. The value of hematopoietic stem cell transplantation (HSCT) for EL is unknown. This EBMT registry study reports on the largest series of patients with EL treated with HSCT in first complete remission-103 aut...

    journal_title:Blood

    pub_type: 杂志文章,多中心研究

    doi:10.1182/blood.V100.9.3135

    authors: Fouillard L,Labopin M,Gorin NC,Polge E,Prentice HG,Meloni G,Reiffers J,Pigneux A,Willemze R,Schattenberg A,Sica S,Lagrange M,Fenneteau O,Perot C,Frassoni F,Acute Leukemia Working Party of the EBMT.

    更新日期:2002-11-01 00:00:00

  • Prostaglandin E2 enhances long-term repopulation but does not permanently alter inherent stem cell competitiveness.

    abstract::Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for malignant and nonmalignant hematologic diseases and metabolic disorders. Although successful, hematopoietic transplantation can be hindered by inadequate stem cell number or poor engrafting efficiency. To overcome these deficits, we and others h...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-07-515288

    authors: Hoggatt J,Mohammad KS,Singh P,Pelus LM

    更新日期:2013-10-24 00:00:00

  • A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction.

    abstract::We show that lentiviral delivery of human gamma-globin gene under beta-globin regulatory control elements in hematopoietic stem cells (HSCs) results in sufficient postnatal fetal hemoglobin (HbF) expression to correct sickle cell anemia (SCA) in the Berkeley "humanized" sickle mouse. Upon de-escalating the amount of t...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2009-01-201863

    authors: Perumbeti A,Higashimoto T,Urbinati F,Franco R,Meiselman HJ,Witte D,Malik P

    更新日期:2009-08-06 00:00:00

  • Granulated T cell lymphocytosis with neutropenia: malignant or benign chronic lymphoproliferative disorder?

    abstract::The clinical, morphological, immunologic, and cytogenetic features of seven cases of chronic granulated T cell lymphocytosis with neutropenia were studied. The disorder was characterized by moderate blood and bone marrow lymphocytosis, neutropenia, polyclonal hypergammaglobulinemia, splenomegaly, absence of lymphadeno...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: McKenna RW,Arthur DC,Gajl-Peczalska KJ,Flynn P,Brunning RD

    更新日期:1985-08-01 00:00:00

  • Δ12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice.

    abstract::Targeting cancer stem cells is of paramount importance in successfully preventing cancer relapse. Recently, in silico screening of public gene-expression datasets identified cyclooxygenase-derived cyclopentenone prostaglandins (CyPGs) as likely agents to target malignant stem cells. We show here that Δ(12)-PGJ(3), a n...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-11-317750

    authors: Hegde S,Kaushal N,Ravindra KC,Chiaro C,Hafer KT,Gandhi UH,Thompson JT,van den Heuvel JP,Kennett MJ,Hankey P,Paulson RF,Prabhu KS

    更新日期:2011-12-22 00:00:00

  • Experimental transmission and pathogenesis of immunodeficiency syndrome in cats.

    abstract::We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infe...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hoover EA,Mullins JI,Quackenbush SL,Gasper PW

    更新日期:1987-12-01 00:00:00

  • Normal iron absorption and decreased red cell iron uptake in the aged.

    abstract::Absorption of iron was studied with a double-isotope technique that allowed differentiation between "mucosal uptake," "mucosal transfer," and ultimate "retention" of iron. A physiologic dose of ferrous sulfate was administered to 25 healthy young adults, 40 active aged persons, and 20 patients with uncomplicated iron ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Marx JJ

    更新日期:1979-02-01 00:00:00

  • Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency.

    abstract::Acquired factor XIII (FXIII) deficiency due to autoantibody against FXIII is a very rare severe hemorrhagic diathesis. Antibodies directed against the A subunit of FXIII, which interfere with different functions of FXIII, have been described. Here, for the first time, we report an autoantibody against the B subunit of...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2008-09-179333

    authors: Ajzner E,Schlammadinger A,Kerényi A,Bereczky Z,Katona E,Haramura G,Boda Z,Muszbek L

    更新日期:2009-01-15 00:00:00

  • Dehydration of mature and immature sickle red blood cells during fast oxygenation/deoxygenation cycles: role of KCl cotransport and extracellular calcium.

    abstract::Sickle red blood cells (RBC) become dehydrated as a consequence of potassium loss. This process depends at least partly on deoxygenation and may be influenced by the presence of oxygenation/deoxygenation cycles and the frequency of cycling. In this study, sickle RBC were subjected to approximately 180 oxygenation/deox...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: McGoron AJ,Joiner CH,Palascak MB,Claussen WJ,Franco RS

    更新日期:2000-03-15 00:00:00

  • Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia.

    abstract::Approximately 40% of children with acute myeloid leukemia (AML) who respond to initial therapy subsequently relapse. Multidimensional flow cytometry employing a standardized panel of monoclonal antibodies enables the detection of small numbers of occult leukemic cells that persist during therapy using technology adapt...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-10-3064

    authors: Sievers EL,Lange BJ,Alonzo TA,Gerbing RB,Bernstein ID,Smith FO,Arceci RJ,Woods WG,Loken MR

    更新日期:2003-05-01 00:00:00

  • Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.

    abstract::Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a firs...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2017-04-779405

    authors: Stein EM,DiNardo CD,Pollyea DA,Fathi AT,Roboz GJ,Altman JK,Stone RM,DeAngelo DJ,Levine RL,Flinn IW,Kantarjian HM,Collins R,Patel MR,Frankel AE,Stein A,Sekeres MA,Swords RT,Medeiros BC,Willekens C,Vyas P,Tosolini A

    更新日期:2017-08-10 00:00:00

  • Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia.

    abstract::Human T-cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease. MicroRNAs (miRNAs) are differentially expressed during hematopoiesis and lineage commitment of hematopoietic stem cell progenitors (HSCPs). Here, we report aberrant expression o...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2008-11-189845

    authors: Bellon M,Lepelletier Y,Hermine O,Nicot C

    更新日期:2009-05-14 00:00:00

  • Genetic heterogeneity in heterocellular hereditary persistence of fetal hemoglobin.

    abstract::A large English pedigree in which heterocellular hereditary persistence of fetal hemoglobin (HPFH) segregates is described. beta-globin cluster deletions and gamma gene promoter mutations associated with HPFH have been excluded. Of particular importance in this pedigree is the absence of any cosegregating hemoglobinop...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Craig JE,Rochette J,Sampietro M,Wilkie AO,Barnetson R,Hatton CS,Demenais F,Thein SL

    更新日期:1997-07-01 00:00:00

  • Cytosolic free calcium changes induced by chemotactic peptide in neutrophils from patients with chronic granulomatous disease.

    abstract::Cytoplasmic free calcium concentration (Ca2+)i was measured in neutrophils from patients with the classical X-linked form of chronic granulomatous disease (CGD) by trapping the fluorescent calcium indicator Quin 2 in intact cells. CGD neutrophils do not produce superoxide and are only slightly depolarized upon stimula...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Lew PD,Wollheim C,Seger RA,Pozzan T

    更新日期:1984-01-01 00:00:00

  • A case-control study to assess the risk of immune thrombocytopenia associated with vaccines.

    abstract::The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hem...

    journal_title:Blood

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1182/blood-2012-05-431098

    authors: Grimaldi-Bensouda L,Michel M,Aubrun E,Leighton P,Viallard JF,Adoue D,Magy-Bertrand N,Tisserand G,Khellaf M,Durand JM,Quittet P,Fain O,Bonnotte B,Morin AS,Limal N,Costedoat-Chalumeau N,Morel N,Pan-Petesch B,Decaux O,

    更新日期:2012-12-13 00:00:00

  • Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis.

    abstract::We have retrospectively assessed the neurological manifestations in 34 patients with hemophagocytic lymphohistiocytosis (HLH) in a single center. Clinical, radiological, and cerebrospinal fluid (CSF) cytology data were analyzed according to treatment modalities. Twenty-five patients (73%) had evidence of central nervo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Haddad E,Sulis ML,Jabado N,Blanche S,Fischer A,Tardieu M

    更新日期:1997-02-01 00:00:00

  • Gadd45a regulates hematopoietic stem cell stress responses in mice.

    abstract::Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a(-/-)) mice showed a normal hematologic phenotype under homeostatic conditions. However, f...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-05-504084

    authors: Chen Y,Ma X,Zhang M,Wang X,Wang C,Wang H,Guo P,Yuan W,Rudolph KL,Zhan Q,Ju Z

    更新日期:2014-02-06 00:00:00

  • Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression.

    abstract::Recent data suggest that CD8+ T-cell effector activity is an important component in the control of HIV replication in elite controllers (ECs). One critical element of CD8+ T-cell effector function and differentiation is the T-box transcription factor T-bet. In the present study, we assessed T-bet expression, together ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-12-322727

    authors: Hersperger AR,Martin JN,Shin LY,Sheth PM,Kovacs CM,Cosma GL,Makedonas G,Pereyra F,Walker BD,Kaul R,Deeks SG,Betts MR

    更新日期:2011-04-07 00:00:00

  • C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors.

    abstract::The transmembrane 4 superfamily (TM4SF) has come into prominence for its association with a wide range of cell surface molecules, especially integrins. We report that TM4SF molecules CD9, CD63, and CD81 are physically associated with c-kit receptor tyrosine kinase in the human factor-dependent myeloid cell line, MO7e....

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v99.12.4413

    authors: Anzai N,Lee Y,Youn BS,Fukuda S,Kim YJ,Mantel C,Akashi M,Broxmeyer HE

    更新日期:2002-06-15 00:00:00

  • Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells.

    abstract::Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient f...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-04-280305

    authors: Khandanpour C,Sharif-Askari E,Vassen L,Gaudreau MC,Zhu J,Paul WE,Okayama T,Kosan C,Möröy T

    更新日期:2010-12-09 00:00:00