Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition.

Abstract:

:For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www.clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL.

journal_name

Blood

journal_title

Blood

authors

Irving J,Matheson E,Minto L,Blair H,Case M,Halsey C,Swidenbank I,Ponthan F,Kirschner-Schwabe R,Groeneveld-Krentz S,Hof J,Allan J,Harrison C,Vormoor J,von Stackelberg A,Eckert C

doi

10.1182/blood-2014-04-531871

subject

Has Abstract

pub_date

2014-11-27 00:00:00

pages

3420-30

issue

23

eissn

0006-4971

issn

1528-0020

pii

blood-2014-04-531871

journal_volume

124

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Variable breakpoints on the Philadelphia chromosome in chronic myelogenous leukemia.

    abstract::The abl oncogene is translocated from chromosome 9 to 22 in the creation of the Philadelphia (Ph1) chromosome. This article describes new translocation breakpoints identified in two patients with chronic myelogenous leukemia using Southern blotting and cloned human DNA probes from chromosome 9. The translocation break...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Leibowitz D,Schaefer-Rego K,Popenoe DW,Mears JG,Bank A

    更新日期:1985-07-01 00:00:00

  • Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis.

    abstract::Cyclic adenosine monophosphate (cAMP) is an important modulator of platelet responses to agonists. Cyclic nucleotide phosphodiesterase (PDE) controls intracellular cAMP concentrations by hydrolyzing it to AMP. The major PDE activity in platelets is PDE3A (cyclic guanosine monophosphate [cGMP]-inhibited PDE). To obtain...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Cheung PP,Xu H,McLaughlin MM,Ghazaleh FA,Livi GP,Colman RW

    更新日期:1996-08-15 00:00:00

  • Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand.

    abstract::Recovery of dendritic cells (DCs) and natural killer (NK) cells after allogeneic stem cell transplantation (SCT) is important for allograft responses and antitumor immunity and thus for treatment outcome. Regulation of this regenerative process is not well understood. We investigated the influence of endogenous cytoki...

    journal_title:Blood

    pub_type: 临床试验,杂志文章

    doi:10.1182/blood-2003-04-1200

    authors: Chklovskaia E,Nowbakht P,Nissen C,Gratwohl A,Bargetzi M,Wodnar-Filipowicz A

    更新日期:2004-05-15 00:00:00

  • Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.

    abstract::Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity....

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Granowitz EV,Porat R,Mier JW,Orencole SF,Callahan MV,Cannon JG,Lynch EA,Ye K,Poutsiaka DD,Vannier E

    更新日期:1993-11-15 00:00:00

  • High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver.

    abstract::Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurre...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2004-12-4689

    authors: Lavoie JC,Connors JM,Phillips GL,Reece DE,Barnett MJ,Forrest DL,Gascoyne RD,Hogge DE,Nantel SH,Shepherd JD,Smith CA,Song KW,Sutherland HJ,Toze CL,Voss NJ,Nevill TJ

    更新日期:2005-08-15 00:00:00

  • Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations.

    abstract::Familial hemophagocytic lymphohistiocytosis (FHL) is caused by genetic defects in cytotoxic granule components or their fusion machinery, leading to impaired natural killer cell and/or T lymphocyte degranulation and/or cytotoxicity. This may accumulate into a life-threatening condition known as macrophage activation s...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-03-494039

    authors: Zhao XW,Gazendam RP,Drewniak A,van Houdt M,Tool AT,van Hamme JL,Kustiawan I,Meijer AB,Janssen H,Russell DG,van de Corput L,Tesselaar K,Boelens JJ,Kuhnle I,Van Der Werff Ten Bosch J,Kuijpers TW,van den Berg TK

    更新日期:2013-07-04 00:00:00

  • Bryostatin 1 induces differentiation of B-chronic lymphocytic leukemia cells.

    abstract::Peripheral blood cells from nine patients with B-chronic lymphocytic leukemia (B-CLL) were treated in vitro with bryostatin 1 (a macrocyclic lactone derived from a marine invertebrate). Like the phorbol ester 12-0-tetradecanoyl-phorbol 13-acetate (TPA), bryostatin 1 activates protein kinase C (PKC), which plays a cent...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Drexler HG,Gignac SM,Jones RA,Scott CS,Pettit GR,Hoffbrand AV

    更新日期:1989-10-01 00:00:00

  • Therapeutic targeting of HES1 transcriptional programs in T-ALL.

    abstract::Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 rem...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-10-608448

    authors: Schnell SA,Ambesi-Impiombato A,Sanchez-Martin M,Belver L,Xu L,Qin Y,Kageyama R,Ferrando AA

    更新日期:2015-04-30 00:00:00

  • X-linked lymphoproliferative syndromes: brothers or distant cousins?

    abstract::X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecu...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2010-03-275909

    authors: Filipovich AH,Zhang K,Snow AL,Marsh RA

    更新日期:2010-11-04 00:00:00

  • Selective activation of TACI by syndecan-2.

    abstract::B-lymphocyte homeostasis and function are regulated by complementary actions of the TNFR family members TACI, BCMA, and BAFF-R, which are expressed by mature B cells. How these receptors are differentially activated is not entirely understood, because the primary ligand BAFF binds to all three. We searched for alterna...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-01-0256

    authors: Bischof D,Elsawa SF,Mantchev G,Yoon J,Michels GE,Nilson A,Sutor SL,Platt JL,Ansell SM,von Bulow G,Bram RJ

    更新日期:2006-04-15 00:00:00

  • Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation.

    abstract::During the course of differentiation of early human myeloid cells toward monocytes and granulocytes, cell surface expression of the cell adhesion molecule, CD11b/CD18 (Mo1) increases dramatically and expression of myeloperoxidase (MPO), a bacteriocidal enzyme, decreases markedly. Using the inducible promyelocytic cell...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Rosmarin AG,Weil SC,Rosner GL,Griffin JD,Arnaout MA,Tenen DG

    更新日期:1989-01-01 00:00:00

  • The effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply.

    abstract::The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Loo M,Beguin Y

    更新日期:1999-05-15 00:00:00

  • The AKT kinase is activated in multiple myeloma tumor cells.

    abstract::Immunohistochemistry (IHC) was performed on archived bone marrow (BM) with a phosphospecific anti-AKT antibody. IHC on 26 BM biopsies from patients with multiple myeloma (MM) demonstrated phospho-AKT staining of malignant plasma cells in a cell membrane-specific pattern, whereas nonmalignant hematopoietic cells did no...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v98.9.2853

    authors: Hsu J,Shi Y,Krajewski S,Renner S,Fisher M,Reed JC,Franke TF,Lichtenstein A

    更新日期:2001-11-01 00:00:00

  • The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.

    abstract::NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3...

    journal_title:Blood

    pub_type: 杂志文章,随机对照试验

    doi:10.1182/blood-2012-05-429282

    authors: Oscier DG,Rose-Zerilli MJ,Winkelmann N,Gonzalez de Castro D,Gomez B,Forster J,Parker H,Parker A,Gardiner A,Collins A,Else M,Cross NC,Catovsky D,Strefford JC

    更新日期:2013-01-17 00:00:00

  • Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts.

    abstract::Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyte-endothelial interactions. A simple...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v97.1.330

    authors: Lühn K,Marquardt T,Harms E,Vestweber D

    更新日期:2001-01-01 00:00:00

  • Intragenic Factor IX restriction site polymorphism in hemophilia B variants.

    abstract::This study includes 47 normal subjects and 25 hemophilia B patients without inhibitor(s), showing different factor IX coagulant activity and antigen levels. Genomic DNA, digested with various restriction endonucleases, was hybridized with two different factor IX probes, ie, the cDNA and the subgenomic probe for the in...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hassan HJ,Orlando M,Leonardi A,Chelucci C,Guerriero R,Mannucci PM,Mariani G,Peschle C

    更新日期:1985-02-01 00:00:00

  • Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation.

    abstract::Cellular oxygen partial pressure is sensed by a family of prolyl-4-hydroxylase domain (PHD) enzymes that modify hypoxia-inducible factor (HIF)alpha subunits. Upon hydroxylation under normoxic conditions, HIFalpha is bound by the von Hippel-Lindau tumor suppressor protein and targeted for proteasomal destruction. Since...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2004-10-3980

    authors: Martin F,Linden T,Katschinski DM,Oehme F,Flamme I,Mukhopadhyay CK,Eckhardt K,Tröger J,Barth S,Camenisch G,Wenger RH

    更新日期:2005-06-15 00:00:00

  • A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin: its application to the measurement of granulocyte-derived elastase digests in plasma.

    abstract::When granulocytes are stimulated under certain clinical conditions, elastase is released therefrom and digests fibrin(ogen) independently of the plasmin system, which may also be mobilized simultaneously. Thus, discrimination of these 2 systems becomes urgent for the diagnosis and treatment of the underlying diseases....

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Kohno I,Inuzuka K,Itoh Y,Nakahara K,Eguchi Y,Sugo T,Soe G,Sakata Y,Murayama H,Matsuda M

    更新日期:2000-03-01 00:00:00

  • Loss of DGKε induces endothelial cell activation and death independently of complement activation.

    abstract::Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-06-579953

    authors: Bruneau S,Néel M,Roumenina LT,Frimat M,Laurent L,Frémeaux-Bacchi V,Fakhouri F

    更新日期:2015-02-05 00:00:00

  • Molecular characterization of commercial porcine factor VIII concentrate.

    abstract::Commercial porcine factor VIII concentrate (Hyate:C) is effective in treatment of patients with hemophilia A who have circulating antibodies to factor VIII. The molecular forms of factor VIII in the concentrate were identified and evaluated in light of the known properties of porcine and human factor VIII. The factor ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Lollar P,Parker CG,Tracy RP

    更新日期:1988-01-01 00:00:00

  • Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in beta2-microglobulin knockout mice.

    abstract::Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (bet...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Santos M,Clevers H,de Sousa M,Marx JJ

    更新日期:1998-04-15 00:00:00

  • Molecular insights into regulation of JAK2 in myeloproliferative neoplasms.

    abstract::The critical role of Janus kinase-2 (JAK2) in regulation of myelopoiesis was established 2 decades ago, but identification of mutations in the pseudokinase domain of JAK2 in myeloproliferative neoplasms (MPNs) and in other hematologic malignancies highlighted the role of JAK2 in human disease. These findings have revo...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2015-01-621110

    authors: Silvennoinen O,Hubbard SR

    更新日期:2015-05-28 00:00:00

  • Biomarkers for prediction of venous thromboembolism in cancer.

    abstract::Cancer patients are at increased risk of deep vein thrombosis and pulmonary embolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. Biomarkers have been specifically investigated for their capacity of predicti...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2013-04-460147

    authors: Pabinger I,Thaler J,Ay C

    更新日期:2013-09-19 00:00:00

  • Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.

    abstract::To identify genes linked to normal plasma cell (PC) differentiation and to classify multiple myeloma (MM) with respect to the expression patterns of these genes, we analyzed global mRNA expression in CD19-enriched B cells (BCs) from 7 tonsils, CD138-enriched PCs from 11 tonsils, 31 normal bone marrow samples, and 74 M...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-06-1737

    authors: Zhan F,Tian E,Bumm K,Smith R,Barlogie B,Shaughnessy J Jr

    更新日期:2003-02-01 00:00:00

  • Donor origin of multipotent adult progenitor cells in radiation chimeras.

    abstract::Multipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells that have extensive in vitro expansion capacity and can differentiate in vivo and in vitro into tissue cells of all 3 germinal layers: ectoderm, mesoderm, and endoderm. The origin of MAPCs within bone marrow is unknown. MAPCs are believed to...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2004-12-4603

    authors: Reyes M,Li S,Foraker J,Kimura E,Chamberlain JS

    更新日期:2005-11-15 00:00:00

  • Recurrent CDKN1B (p27) mutations in hairy cell leukemia.

    abstract::Hairy cell leukemia (HCL) is marked by near 100% mutational frequency of BRAFV600E mutations. Recurrent cooperating genetic events that may contribute to HCL pathogenesis or affect the clinical course of HCL are currently not described. Therefore, we performed whole exome sequencing to explore the mutational landscape...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2015-04-643361

    authors: Dietrich S,Hüllein J,Lee SC,Hutter B,Gonzalez D,Jayne S,Dyer MJ,Oleś M,Else M,Liu X,Słabicki M,Wu B,Troussard X,Dürig J,Andrulis M,Dearden C,von Kalle C,Granzow M,Jauch A,Fröhling S,Huber W,Meggendorfer M,Hafe

    更新日期:2015-08-20 00:00:00

  • Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).

    abstract::Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which venous thrombosis is the most common cause of death. Here we address the risk factors for thrombosis and the role of warfarin prophylaxis in PNH. The median follow-up of 163 PNH patients was 6 years (range, 0.2-38 years). Of the patient...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-01-0009

    authors: Hall C,Richards S,Hillmen P

    更新日期:2003-11-15 00:00:00

  • Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma.

    abstract::Bacterial DNA and synthetic oligodeoxynucleotides containing the CpG motif (CpG ODN) can activate various immune cell subsets, including natural killer cells and macrophages. We evaluated whether the combination of CpG ODN and antitumor monoclonal antibody is effective at preventing tumor growth in an immunocompetent ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Wooldridge JE,Ballas Z,Krieg AM,Weiner GJ

    更新日期:1997-04-15 00:00:00

  • Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation.

    abstract::Monocytes regulate host defenses, inflammation, and tissue homeostasis. The transcription factor interferon regulatory factor-8 (IRF8) stimulates monocyte/macrophage differentiation, yet genome-wide understanding of the differentiation program initiated by IRF8 is lacking. By combining chromatin immunoprecipitation se...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2012-06-437863

    authors: Kurotaki D,Osato N,Nishiyama A,Yamamoto M,Ban T,Sato H,Nakabayashi J,Umehara M,Miyake N,Matsumoto N,Nakazawa M,Ozato K,Tamura T

    更新日期:2013-03-07 00:00:00

  • Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation.

    abstract::Twenty-six patients with progressive Hodgkin's disease after conventional chemotherapy received intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT); 19 also received additional involved-field radiotherapy. Twenty-one patients [81%, 95% confidence intervals (CI) 61% to 94%] attained complete (...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Phillips GL,Wolff SN,Herzig RH,Lazarus HM,Fay JW,Lin HS,Shina DC,Glasgow GP,Griffith RC,Lamb CW

    更新日期:1989-06-01 00:00:00