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
















  • N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity.

    abstract::The in vitro effects of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR, fenretinide) on primary B-cell chronic lymphocytic leukemia (CLL) cells from previously untreated CLL patients were investigated. 4HPR promoted the intrinsic apoptotic pathway by reactive oxygen species (ROS) generation and was accompa...


    pub_type: 杂志文章


    authors: Bruno S,Ghiotto F,Tenca C,Mazzarello AN,Bono M,Luzzi P,Casciaro S,Recchia A,Decensi A,Morabito F,Fais F

    更新日期:2012-10-01 00:00:00

  • Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11) - a report of the Children's Cancer Group.

    abstract::Infants less than 1 year of age at diagnosis of acute lymphoblastic leukemia (ALL) have a poor prognosis, which has been attributed primarily to a breakpoint in chromosomal band 11q23 or the MLL gene. Most infants with an 11q23 breakpoint have a t(4;11)(q21 ;q23). We studied the cytogenetics of the leukemia cells of 5...


    pub_type: 杂志文章


    authors: Heerema NA,Sather HN,Ge J,Arthur DC,Hilden JM,Trigg ME,Reaman GH

    更新日期:1999-05-01 00:00:00

  • Activation of Harvey ras oncogene by mutation at codon 12 is very rare in hemopoietic malignancies.

    abstract::Point mutations within codon 12 of the Harvey (H-) ras proto-oncogene have recently been implicated in the progression of hemopoietic malignancy, particularly chronic myeloid leukemia. We have analyzed DNA from 170 cases of acute and chronic leukemia by using a restriction fragment length polymorphism. No evidence for...


    pub_type: 杂志文章


    authors: Browett PJ,Yaxley JC,Norton JD

    更新日期:1989-01-01 00:00:00

  • Human bone marrow cytogenetics: growth factors stimulate metaphases for specific lineages.

    abstract::Fresh and/or frozen bone marrow cells from five healthy individuals and seven patients with myeloid leukemia were studied using growth factors and a cytogenetic technique which allows simultaneous analysis of karotype and cell lineage. Cell lineages were identified using monoclonal antibodies in an alkaline phosphatas...


    pub_type: 杂志文章


    authors: Keinänen M,Bloomfield CD,Machnicki J,Griffin JD,de la Chapelle A

    更新日期:1989-06-01 00:00:00

  • A paradigm shift in myelodysplastic syndromes.

    abstract::A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propo...


    pub_type: 杂志文章,评审


    authors: Raza A,Mundle S,Shetty V,Alvi S,Chopra H,Span L,Parcharidou A,Dar S,Venugopal P,Borok R,Gezer S,Showel J,Loew J,Robin E,Rifkin S,Alston D,Hernandez B,Shah R,Kaizer H,Gregory S,Preisler H

    更新日期:1996-10-01 00:00:00

  • TCR gamma/delta bearing lymphocytes in peripheral blood of allogenic bone marrow transplanted patients.

    abstract::The presence of two distinct T-cell receptors (TCR) alpha/beta and gamma/delta dimers as well as of the activated T cells was analysed in peripheral blood mononuclear cells from seventeen recipients of allogeneic bone marrow transplants for leukemia and for severe aplastic anemia. Nine of seventeen recipients expresse...


    pub_type: 杂志文章


    authors: Pálóczi K,Poros A,Szelényi J,Hollán SR,Petrányi GG

    更新日期:1992-01-01 00:00:00

  • Is t(14;18)(q32;q21) a constant finding in follicular lymphoma? An interphase FISH study on 63 patients.

    abstract::The translocation (14;18)(q32;q21) is the hallmark of follicular lymphoma (FL). However, conventional cytogenetics and PCR techniques fail to detect it in at least 10% of cases. In order to evaluate the true incidence of this translocation in FL, we analyzed 63 patients with FL, and 17 patients with diffuse large cell...


    pub_type: 杂志文章


    authors: Godon A,Moreau A,Talmant P,Baranger-Papot L,Geneviève F,Milpied N,Zandecki M,Avet-Loiseau H

    更新日期:2003-01-01 00:00:00

  • Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-AL

    abstract::A total of 28 children and nine adults with relapsed T-ALL were analyzed for the configuration of their T-cell receptor (TCR) and TAL1 genes at diagnosis and relapse to evaluate their stability throughout the disease course. A total of 150 clonal TCR and TAL1 gene rearrangements were identified in the 37 patients at d...


    pub_type: 杂志文章


    authors: Szczepański T,van der Velden VH,Raff T,Jacobs DC,van Wering ER,Brüggemann M,Kneba M,van Dongen JJ

    更新日期:2003-11-01 00:00:00

  • Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis.

    abstract::Peripheral arterial occlusive disease (PAOD) occurs in patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs). The risk of developing PAOD on TKI therapy is unknown and causality has not been established. Patients with CML-CP from three randomized phase III studies...


    pub_type: 杂志文章


    authors: Giles FJ,Mauro MJ,Hong F,Ortmann CE,McNeill C,Woodman RC,Hochhaus A,le Coutre PD,Saglio G

    更新日期:2013-06-01 00:00:00

  • Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) stu

    abstract::Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, af...


    pub_type: 杂志文章,多中心研究


    authors: Jovanovic JV,Ivey A,Vannucchi AM,Lippert E,Oppliger Leibundgut E,Cassinat B,Pallisgaard N,Maroc N,Hermouet S,Nickless G,Guglielmelli P,van der Reijden BA,Jansen JH,Alpermann T,Schnittger S,Bench A,Tobal K,Wilkins B,Cu

    更新日期:2013-10-01 00:00:00

  • Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes.

    abstract::About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two pa...


    pub_type: 杂志文章


    authors: Raghoebier S,Broos L,Kramer MH,van Krieken JH,Kluin-Nelemans JC,van Ommen GJ,Kluin P

    更新日期:1995-10-01 00:00:00

  • Pharmacokinetics of idarubicin after oral administration in elderly leukemic patients.

    abstract::We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy daunorubicin) in 11 elderly patients suffering from acute myeloblastic leukemia receiving orally 30 mg/m2 per day for 3 consecutive days. Idarubicin culminated in plasma 4 hr after administration and followed three similar time courses after the th...


    pub_type: 临床试验,杂志文章,多中心研究


    authors: Robert J,Rigal-Huguet F,Huet S,Pris J,Hurteloup P

    更新日期:1990-03-01 00:00:00

  • Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells.

    abstract::The cyclin-dependent kinase inhibitors known as p15, p16, p18 and p19 have been suggested as candidates for tumor suppressor genes. The main genetic alterations are deletions (bi- or monoallelic) or 5' CpG island methylation of p15 and p16; very few cases or cell lines had p18 or p19 deletions or hypermethylation. Hyp...


    pub_type: 杂志文章,评审


    authors: Drexler HG

    更新日期:1998-06-01 00:00:00

  • The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF.

    abstract::GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common beta chain (beta c) of the GM-CSF receptor to produce mice with constitutively elevated GM-CSF levels but no high-affinity GM-CSF receptors. GM-CSF transgenic beta c -/- mice had exceptionally elevated serum GM-C...


    pub_type: 杂志文章


    authors: Metcalf D,Mifsud S,Di Rago L,Robb L,Nicola NA,Alexander W

    更新日期:1998-03-01 00:00:00

  • CD34(+) or CD34(-): which is the more primitive?

    abstract::Remarkable progress has been achieved in the characterization and isolation of primitive hematopoietic stem cells (HSC). HSC represent a very small subset of hematopoietic cells and provide self-renewal, possess differentiation capacity and allow a constant supply of the entire hematopoietic cell spectrum. Until recen...


    pub_type: 杂志文章,评审


    authors: Engelhardt M,Lübbert M,Guo Y

    更新日期:2002-09-01 00:00:00

  • Transplantation of stromal cells transduced with the human IL3 gene to stimulate hematopoiesis in human fetal bone grafts in non-obese, diabetic-severe combined immunodeficiency mice.

    abstract::The non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mouse is a convenient host for human hematopoietic tissues and cells. Human fetal bone fragments engrafted subcutaneously in NOD-SCID mice sustain human hematopoiesis for several months. MS5 murine bone marrow stromal cells were transfected by electrop...


    pub_type: 杂志文章


    authors: Brouard N,Chapel A,Neildez-Nguyen TM,Granotier C,Khazaal I,Péault B,Thierry D

    更新日期:1998-07-01 00:00:00

  • Collection, analysis and transplantation of Ph-negative blood precursor cells in chronic myeloid leukemia.

    abstract::This work represents an update of our experience on mobilization and transplantation of peripheral blood progenitor cells (PBPC) collected during the early recovery phase after chemotherapy in patients with chronic myelogenous leukemia. The collection of Ph-negative precursor cells occurred in 13/19 (68%) patients mob...


    pub_type: 杂志文章


    authors: Frassoni F,Carella AM

    更新日期:1996-06-01 00:00:00

  • t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia.

    abstract::Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Rese...


    pub_type: 杂志文章


    authors: Krance RA,Raimondi SC,Dubowy R,Estrada J,Borowitz M,Behm F,Land VJ,Pullen J,Carroll AJ

    更新日期:1992-04-01 00:00:00

  • Resistance to RadLV-induced leukemia: non-participation of splenic natural killer cells.

    abstract::The phenotypic expression of genetically determined resistance to radiation leukemia virus (RadLV)-induced leukemia in mice has been shown to reside in the bone marrow. Because the bone marrow contains precursors of natural killer (NK) cells, known to play a role in retrovirally induced infections, and because these c...


    pub_type: 杂志文章


    authors: St-Pierre Y,Hugo P,Lemieux S,Lussier G,Potworowski EF

    更新日期:1988-08-01 00:00:00

  • An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia.

    abstract::The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tu...


    pub_type: 杂志文章


    authors: Angenendt L,Reuter S,Kentrup D,Benk AS,Neumann F,Hüve J,Martens AC,Schwöppe C,Kessler T,Schmidt LH,Sauer T,Brand C,Mikesch JH,Lenz G,Mesters RM,Müller-Tidow C,Hartmann W,Wardelmann E,Neri D,Berdel WE,Roesli C,Sc

    更新日期:2018-02-01 00:00:00

  • The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts.

    abstract::Refractory anemia with ring sideroblasts (RARS) is characterized by mitochondrial ferritin (FTMT) accumulation and markedly suppressed expression of the iron transporter ABCB7. To test the hypothesis that ABCB7 is a key mediator of ineffective erythropoiesis of RARS, we modulated its expression in hematopoietic cells....


    pub_type: 杂志文章


    authors: Nikpour M,Scharenberg C,Liu A,Conte S,Karimi M,Mortera-Blanco T,Giai V,Fernandez-Mercado M,Papaemmanuil E,Högstrand K,Jansson M,Vedin I,Wainscoat JS,Campbell P,Cazzola M,Boultwood J,Grandien A,Hellström-Lindberg E

    更新日期:2013-04-01 00:00:00

  • Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells.

    abstract::Arsenic trioxide (ATO) induces disease remission in acute promyelocytic leukemia (APL) patients, but not in non-APL acute myeloid leukemia (AML) patients. ATO at therapeutic concentrations (1-2 μM) induces APL NB4, but not non-APL HL-60, cells to undergo apoptosis through the mitochondrial pathway. The role of antiapo...


    pub_type: 杂志文章


    authors: Wang R,Xia L,Gabrilove J,Waxman S,Jing Y

    更新日期:2013-02-01 00:00:00

  • Ionising radiation and leukaemia potential risks: review based on the workshop held during the 10th Symposium on Molecular Biology of Hematopoiesis and Treatment of Leukemia and Lymphomas at Hamburg, Germany on 5 July 1997.

    abstract::Unexplained clusters of childhood leukaemia have generated concern that they may be causally related to environmental exposure to ionising radiation. The workshop provides in-depth examination of the aetiology of childhood leukaemia, patterns of clustering exhibited by cases and the influence of exposure to ionising r...


    pub_type: 杂志文章,评审


    authors: Alexander FE,Greaves MF

    更新日期:1998-08-01 00:00:00

  • Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome.

    abstract::We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment fail...


    pub_type: 杂志文章


    authors: de Lima M,Champlin RE,Thall PF,Wang X,Martin TG 3rd,Cook JD,McCormick G,Qazilbash M,Kebriaei P,Couriel D,Shpall EJ,Khouri I,Anderlini P,Hosing C,Chan KW,Andersson BS,Patah PA,Caldera Z,Jabbour E,Giralt S

    更新日期:2008-02-01 00:00:00

  • Incomplete DJH rearrangements of the IgH gene are frequent in multiple myeloma patients: immunobiological characteristics and clinical implications.

    abstract::DH-JH rearrangements of the Ig heavy-chain gene (IGH) occur early during B-cell development. Consequently, they are detected in precursor-B-cell acute lymphoblastic leukemias both at diagnosis and relapse. Incomplete DJH rearrangements have also been occasionally reported in mature B-cell lymphoproliferative disorders...


    pub_type: 杂志文章


    authors: González D,Balanzategui A,García-Sanz R,Gutiérrez N,Seabra C,van Dongen JJ,González M,San Miguel JF

    更新日期:2003-07-01 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

  • Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts.

    abstract::The inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting resu...


    pub_type: 杂志文章


    authors: Guerrasio A,Pilatrino C,De Micheli D,Cilloni D,Serra A,Gottardi E,Parziale A,Marmont F,Diverio D,Divona M,Lo Coco F,Saglio G

    更新日期:2002-06-01 00:00:00

  • Changes in peripheral blood and bone marrow specimens during and after alpha 2b-interferon therapy for hairy cell leukemia.

    abstract::We studied changes in peripheral blood and bone marrow biopsy specimens obtained before, during, and after recombinant alpha 2b-interferon (IFN-alpha 2b) therapy in 25 patients with hairy cell leukemia. During therapy, only 1 patient showed no improvement in at least one of the parameters monitored. Granulocytopenia, ...


    pub_type: 杂志文章


    authors: Bardawil RG,Ratain MJ,Golomb HM,Bitter MA,Groves C,Vardiman JW

    更新日期:1987-04-01 00:00:00

  • KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements.

    abstract::Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through...


    pub_type: 杂志文章


    authors: Au YZ,Gu M,De Braekeleer E,Gozdecka M,Aspris D,Tarumoto Y,Cooper J,Yu J,Ong SH,Chen X,Tzelepis K,Huntly BJP,Vassiliou G,Yusa K

    更新日期:2020-08-06 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