Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity.


:Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.






Callahan KP,Minhajuddin M,Corbett C,Lagadinou ED,Rossi RM,Grose V,Balys MM,Pan L,Jacob S,Frontier A,Grever MR,Lucas DM,Kinghorn AD,Liesveld JL,Becker MW,Jordan CT




Has Abstract


2014-10-01 00:00:00
















  • Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML).

    abstract::Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate- or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favorable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), bu...


    pub_type: 杂志文章,多中心研究


    authors: Pigneux A,Labopin M,Maertens J,Cordonnier C,Volin L,Socié G,Blaise D,Craddock C,Milpied N,Bacher U,Malard F,Esteve J,Nagler A,Mohty M,Acute Leukemia Working Party EBMT.

    更新日期:2015-12-01 00:00:00

  • Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation.

    abstract::Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to de...


    pub_type: 杂志文章


    authors: Zeiser R,Spyridonidis A,Wäsch R,Ihorst G,Grüllich C,Bertz H,Finke J

    更新日期:2005-05-01 00:00:00

  • Deletions on der(9) chromosome in adult Ph-positive acute lymphoblastic leukemia occur with a frequency similar to that observed in chronic myeloid leukemia.

    abstract::The t(9;22)(q34;q11), generating the Philadelphia chromosome (Ph), is found in more than 90% of patients with chronic myeloid leukemia (CML) and in 15-30% of adults with acute lymphoblastic leukemia (ALL). Different groups have recently described the presence of large genomic deletions adjacent to the translocation br...


    pub_type: 杂志文章


    authors: Specchia G,Albano F,Anelli L,Storlazzi CT,Zagaria A,Mancini M,Cuneo A,Pane F,Foà R,Manolelli F,Liso V,Rocchi M

    更新日期:2003-03-01 00:00:00

  • Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha.

    abstract::Signal transducer and activator of transcription (Stat)3 is constitutively activated in cutaneous T-cell lymphoma (CTCL), where it protects tumour cells against apoptosis. The constitutive activation of Stat3 leads to a constitutive expression of suppressor of cytokine signalling (SOCS)-3. In healthy cells, SOCS-3 is ...


    pub_type: 杂志文章


    authors: Brender C,Lovato P,Sommer VH,Woetmann A,Mathiesen AM,Geisler C,Wasik M,Ødum N

    更新日期:2005-02-01 00:00:00

  • Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia.

    abstract::It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this stu...


    pub_type: 杂志文章


    authors: Woiciechowsky A,Regn S,Kolb HJ,Roskrow M

    更新日期:2001-02-01 00:00:00

  • CD44 isoforms distinguish between bone marrow plasma cells from normal individuals and patients with multiple myeloma at different stages of disease.

    abstract::CD44 variant isoforms (CD44v) have been shown to be important factors in adverse prognosis in hematological malignancies. To investigate whether CD44 expression is associated with malignant transformation in multiple myeloma, RNA and protein expression of CD44 standard (CD44s) and CD44v4, v6, v9, v10 containing isofor...


    pub_type: 杂志文章


    authors: van Driel M,Günthert U,Stauder R,Joling P,Lokhorst HM,Bloem AC

    更新日期:1998-11-01 00:00:00

  • Correction: Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients.

    abstract::Following the publication of this article, the authors noted that Patrick M. Vanderboom was inadvertently omitted from the author list. The correct author list is as follows: Sanjay Kumar, David Murray, Surendra Dasari, Paolo Milani, David Barnidge, Benjamin Madden, Patrick M. Vanderboom, Taxiarchis Kourelis, Bonnie A...


    pub_type: 已发布勘误


    authors: Kumar S,Murray D,Dasari S,Milani P,Barnidge D,Madden B,Kourelis T,Arendt B,Merlini G,Ramirez-Alvarado M,Dispenzieri A

    更新日期:2019-04-01 00:00:00

  • Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients.

    abstract::The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induce...


    pub_type: 杂志文章


    authors: Iacobucci I,Lonetti A,Messa F,Ferrari A,Cilloni D,Soverini S,Paoloni F,Arruga F,Ottaviani E,Chiaretti S,Messina M,Vignetti M,Papayannidis C,Vitale A,Pane F,Piccaluga PP,Paolini S,Berton G,Baruzzi A,Saglio G,Baccar

    更新日期:2010-01-01 00:00:00

  • A new specific chromosomal rearrangement, t(11;20)(p15;q11), in myeloblastic leukemia with maturation.

    abstract::The translocation t(11;20)(p15;q11) was found as the sole acquired clonal chromosome abnormality in two patients with acute myeloid leukemia. The bone marrow morphology in both cases corresponded to the M2 subtype of the French-American-British (FAB) classification. None of the patients achieved complete remission, an...


    pub_type: 杂志文章


    authors: Mitelman F,Prigogina EL,Fleischman EW,Frenkel MA,Garwicz S,Heim S,Ilyinskaya GW,Kristoffersson U,Mandahl N,Volkova MA

    更新日期:1988-07-01 00:00:00

  • Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines.

    abstract::The Bcr/Abl tyrosine kinase that is expressed from the Philadelphia chromosome protects leukemia cells from apoptosis caused by removal of growth factors or by cytotoxic agents and ionizing irradiation. This resistance to apoptosis is associated with a Bcr/Abl-mediated G2/M delay. Therefore, inhibiting Bcr/Abl signali...


    pub_type: 杂志文章


    authors: Sahin MB,Perman SM,Jenkins G,Clark SS

    更新日期:1999-10-01 00:00:00

  • Basic fibroblast growth factor and hematopoiesis.

    abstract::Basic fibroblast growth factor (bFGF or FGF-2) is an angiogenic and pleiotropic factor involved in the proliferation and differentiation of numerous cell types. It is expressed mostly in tissues of mesoderm and neuroectoderm origin, and plays an important role in the mesoderm induction, together with transforming grow...


    pub_type: 杂志文章,评审


    authors: Allouche M

    更新日期:1995-06-01 00:00:00

  • Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP-EBMT analysis.

    abstract::To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1...


    pub_type: 杂志文章,多中心研究


    authors: Ruggeri A,Michel G,Dalle JH,Caniglia M,Locatelli F,Campos A,de Heredia CD,Mohty M,Hurtado JM,Bierings M,Bittencourt H,Mauad M,Purtill D,Cunha R,Kabbara N,Gluckman E,Labopin M,Peters C,Rocha V

    更新日期:2012-12-01 00:00:00

  • Late effects in survivors of infant leukemia.

    abstract::Little is known about the incidence of and risk factor for late effects of infant leukemia. We evaluated 19 children with acute lymphoblastic leukemia and 15 with acute myeloid leukemia who were diagnosed at age 12 months or younger and have survived for more than 5 years after the diagnosis (median length of follow-u...


    pub_type: 杂志文章


    authors: Leung W,Hudson M,Zhu Y,Rivera GK,Ribeiro RC,Sandlund JT,Bowman LC,Evans WE,Kun L,Pui CH

    更新日期:2000-07-01 00:00:00

  • Effect of the protein kinase C activating agent bryostatin 1 on the clonogenic response of leukemic blast progenitors to recombinant granulocyte-macrophage colony-stimulating factor.

    abstract::Bryostatin 1 is a macrocyclic lactone activator of protein kinase C which has displayed promising antileukemic potential in pre-clinical studies. We have assessed the effect of bryostatin 1 on the in vitro clonogenic response of leukemic myeloblasts obtained from 12 patients with acute non-lymphocytic leukemia to reco...


    pub_type: 杂志文章


    authors: Grant S,Pettit GR,Howe C,McCrady C

    更新日期:1991-05-01 00:00:00

  • BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996).

    abstract::Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of pati...


    pub_type: 临床试验,杂志文章,多中心研究,随机对照试验


    authors: Kamps WA,Bökkerink JP,Hakvoort-Cammel FG,Veerman AJ,Weening RS,van Wering ER,van Weerden JF,Hermans J,Slater R,van den Berg E,Kroes WG,van der Does-van den Berg A

    更新日期:2002-06-01 00:00:00

  • In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis.

    abstract::Fludarabine phosphate (2-F-ara-AMP) is an adenine nucleoside analogue that shows significant activity against chronic lymphocytic leukemia and indolent lymphoma. We assessed the cytotoxic interaction produced by the combination of the active metabolite of fludarabine phosphate, fludarabine (9-beta-D-arabinofuranosyl-2...


    pub_type: 杂志文章


    authors: Kano Y,Akutsu M,Tsunoda S,Suzuki K,Ichikawa A,Furukawa Y,Bai L,Kon K

    更新日期:2000-03-01 00:00:00

  • Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia.

    abstract::Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-naï...


    pub_type: 杂志文章


    authors: Motta M,Rassenti L,Shelvin BJ,Lerner S,Kipps TJ,Keating MJ,Wierda WG

    更新日期:2005-10-01 00:00:00

  • A phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia: results from CALGB Study 9211.

    abstract::Cladribine has been reported to have little activity in fludarabine- refractory chronic lymphocytic leukemia (CLL). We sought to determine whether resistance to therapy with cladribine in fludarabine-refractory CLL patients represented primary drug resistance or the inability to tolerate the myelosuppression associate...


    pub_type: 临床试验,杂志文章,多中心研究


    authors: Byrd JC,Peterson B,Piro L,Saven A,Vardiman JW,Larson RA,Schiffer C

    更新日期:2003-02-01 00:00:00

  • Identification of CD34+ cells in normal and pathological bone marrow biopsies by QBEND10 monoclonal antibody.

    abstract::Monoclonal antibody QBEND10 is reactive with the CD34 antigen in aldehyde-fixed, decalcified, paraffin-embedded bone marrow biopsies. In normal bone marrow it stained endothelial cells lining arterioles and capillaries, sinusoidal (littoral) cells and 0.89% of all haemopoietic cells. QBEND10+ mononuclear cells were se...


    pub_type: 杂志文章


    authors: Soligo D,Delia D,Oriani A,Cattoretti G,Orazi A,Bertolli V,Quirici N,Deliliers GL

    更新日期:1991-12-01 00:00:00

  • Simple and reliably sensitive diagnosis and monitoring of Philadelphia chromosome-positive cells in chronic myeloid leukemia by interphase fluorescence in situ hybridization of peripheral blood cells.

    abstract::Philadelphia (Ph) chromosome or the bcr/abl fusion gene is the hallmark of chronic myeloid leukemia (CML) and serves as a prognostic marker during its treatment. Its detection has been primarily done by karyotype analysis of bone marrow cells. The major limitation of the karyotypic technique is an absolute need for me...


    pub_type: 杂志文章


    authors: Yanagi M,Shinjo K,Takeshita A,Tobita T,Yano K,Kobayashi M,Terasaki H,Naoe T,Ohnishi K,Ohno R

    更新日期:1999-04-01 00:00:00

  • Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia.

    abstract::Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligat...


    pub_type: 杂志文章


    authors: Pfeifer H,Lange T,Wystub S,Wassmann B,Maier J,Binckebanck A,Giagounidis A,Stelljes M,Schmalzing M,Dührsen U,Wunderle L,Serve H,Brück P,Schmidt A,Hoelzer D,Ottmann OG

    更新日期:2012-07-01 00:00:00

  • Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification.

    abstract::In spite of distinct clinical importance, the molecular mechanisms how Additional sex combs-like 1 (ASXL1) mutation contributes to the pathogenesis of premalignant conditions are largely unknown. Here, with newly generated knock-in mice, we investigated the biological effects of the mutant. Asxl1G643fs heterozygous (A...


    pub_type: 杂志文章


    authors: Uni M,Masamoto Y,Sato T,Kamikubo Y,Arai S,Hara E,Kurokawa M

    更新日期:2019-01-01 00:00:00

  • Heterogeneity of HIV-1 replication and antigen expression in EBV-transformed B cell lines.

    abstract::Over a period of six months, we have followed a total of six different EBV-transformed B cell lines, each of which has been infected by the human immunodeficiency virus (HIV-1). The results indicate that all of these lines were initially able to produce progeny HIV-1, but that over time three of them ceased to produce...


    pub_type: 杂志文章


    authors: Tremblay M,Fitz-Gibbon L,Wainberg MA

    更新日期:1988-12-01 00:00:00

  • The (2;5)(p23;q35) translocation in cell lines derived from malignant lymphomas: absence of t(2;5) in Hodgkin-analogous cell lines.

    abstract::The CD30+ anaplastic large cell lymphoma (ALCL) represents a new lymphoma entity thought to be related to Hodgkin'S disease (HD), but displaying also its own unique features. Cytogenetic studies of ALCL have demonstrated the presence of a (2;5)(p23;q35) translocation in a substantial number of these cases. Recently, t...


    pub_type: 杂志文章


    authors: Dirks WG,Zaborski M,Jäger K,Challier C,Shiota M,Quentmeier H,Drexler HG

    更新日期:1996-01-01 00:00:00

  • Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.

    abstract::Membrane-derived vesicles (MV) are released from the surface of activated eucaryotic cells and exert pleiotropic effects on surrounding cells. Since the maintenance of pluripotency and undifferentiated propagation of embryonic stem (ES) cells in vitro requires tight cell to cell contacts and effective intercellular si...


    pub_type: 杂志文章


    authors: Ratajczak J,Miekus K,Kucia M,Zhang J,Reca R,Dvorak P,Ratajczak MZ

    更新日期:2006-05-01 00:00:00

  • Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002.

    abstract::Novel approaches have been designed to treat leukemia based on our understanding of the genetic and biochemical lesions present in different malignancies. This meeting report summarizes some of the recent advances in leukemia treatment. Based on the discoveries of cellular oncogenes, chromosomal translocations, monocl...




    authors: Larson RA,Daley GQ,Schiffer CA,Porcu P,Pui CH,Marie JP,Steelman LS,Bertrand FE,McCubrey JA

    更新日期:2003-12-01 00:00:00

  • De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance.

    abstract::Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic syndromes. Dysplastic features in one or more lineages are also found frequently in bone marrow aspirates from patients with de novo AML and have been associated with an unfavorable prognosis. We asked whether dyshematopoiesis is an independent ...


    pub_type: 杂志文章


    authors: Gahn B,Haase D,Unterhalt M,Drescher M,Schoch C,Fonatsch C,Terstappen LW,Hiddemann W,Büchner T,Bennett JM,Wörmann B

    更新日期:1996-06-01 00:00:00

  • Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity.

    abstract::Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor progn...


    pub_type: 杂志文章


    authors: Andreasson P,Höglund M,Jonson T,Békàssy A,Mitelman F,Johansson B

    更新日期:1998-09-01 00:00:00

  • Minimally differentiated acute myeloid leukemia in Taiwan: predominantly occurs in children less than 3 years and adults between 51 and 70 years.

    abstract::Acute myeloid leukemia (AML) with minimal differentiation was usually referred to as acute undifferentiated leukemia in the past. With the help of immunophenotyping, this subtype of leukemia was shown to express myeloid antigens on the blasts and was designated AML-M0 by FAB Cooperative Study Group in 1991. Among the ...


    pub_type: 临床试验,杂志文章


    authors: Huang SY,Tang JL,Jou ST,Tsay W,Hu CH,Lin DT,Lin KS,Lin KS,Wang CH,Chen YC,Shen MC,Tien HF

    更新日期:1999-10-01 00:00:00

  • Childhood monosomy 7 syndrome: clinical and in vitro studies.

    abstract::The clinical and cell growth characteristics of 11 children with monosomy 7 presenting as preleukemia (eight cases) or acute nonlymphoblastic leukemia (three cases) were studied. Anemia was common to all patients, with nine showing leukocytosis, seven thrombocytopenia, and one thrombocytosis. There was a striking pred...


    pub_type: 杂志文章


    authors: Weiss K,Stass S,Williams D,Kalwinsky D,Dahl GV,Wang W,Johnson FL,Murphy SB,Dow LW

    更新日期:1987-02-01 00:00:00