Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM.

Abstract:

:New drugs are needed for the treatment of relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (combination index <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over that achieved by a single drug alone. Dosing of dexamethasone and selumetinib singly and in combination in mice engrafted with primary-derived RAS pathway-mutated leukemia cells resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukemia burden showed a significant reduction in the drug-treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway-mutated acute lymphoblastic leukemia. An international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway in children with multiply relapsed/refractory disease.

journal_name

Haematologica

journal_title

Haematologica

authors

Matheson EC,Thomas H,Case M,Blair H,Jackson RK,Masic D,Veal G,Halsey C,Newell DR,Vormoor J,Irving JAE

doi

10.3324/haematol.2017.185975

subject

Has Abstract

pub_date

2019-09-01 00:00:00

pages

1804-1811

issue

9

eissn

0390-6078

issn

1592-8721

pii

haematol.2017.185975

journal_volume

104

pub_type

杂志文章
  • Estimating the impact of rituximab on bcl-2-associated resistance to CHOP in elderly patients with diffuse large B-cell lymphoma.

    abstract::Rituximab plus CHOP (R-CHOP) has been proven to increase overall survival in aggressive bcl-2-positive lymphoma patients. Using competing risk analysis, we studied the long-term impact of this treatment in patients from a GELA trial: R-CHOP prevented from progression or relapse in both bcl-2-positive and bcl-2-negativ...

    journal_title:Haematologica

    pub_type: 信件

    doi:

    authors: Mounier N,Briere J,Gisselbrecht C,Reyes F,Gaulard P,Coiffier B,Groupe d'Etude des Lymphomes de l'Adulte.

    更新日期:2006-05-01 00:00:00

  • The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34+CD123+ cells from acute myeloid leukemia/myelodysplastic syndrome patients and healthy donors.

    abstract::Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or h...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2018.188193

    authors: Mani R,Goswami S,Gopalakrishnan B,Ramaswamy R,Wasmuth R,Tran M,Mo X,Gordon A,Bucci D,Lucas DM,Mims A,Brooks C,Dorrance A,Walker A,Blum W,Byrd JC,Lozanski G,Vasu S,Muthusamy N

    更新日期:2018-08-01 00:00:00

  • Dendritic cells: specialized antigen presenting cells.

    abstract::Renewing interest in cancer immunotherapy reflects the excellent results that have been obtained in animal models and the promising results in early clinical trails with dendritic cell (DC) based approaches. The central role that DCs play in the initiation of an immune response raises the possibility of using them to ...

    journal_title:Haematologica

    pub_type: 杂志文章,评审

    doi:

    authors: Di Nicola M,Lemoli RM

    更新日期:2000-02-01 00:00:00

  • Recombinant interferon alpha-2B for acute post-transfusion hepatitis in acute myeloid leukemia.

    abstract::Post-transfusion hepatitis (PTH) is a major problem in patients with acute leukemias requiring blood products during induction or consolidation therapy. In fact, PTH causes delays of chemotherapy with major violations in the timing of protocols. In order to assess the efficacy and safety of a short course of alpha-int...

    journal_title:Haematologica

    pub_type: 临床试验,杂志文章

    doi:

    authors: Almasio P,Mirto S,Malleo C,Di Marco V,Caronia F,Craxi A

    更新日期:1991-09-01 00:00:00

  • Atherogenic lipid stress induces platelet hyperactivity through CD36-mediated hyposensitivity to prostacyclin: the role of phosphodiesterase 3A.

    abstract::Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signaling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2018.213348

    authors: Berger M,Raslan Z,Aburima A,Magwenzi S,Wraith KS,Spurgeon BEJ,Hindle MS,Law R,Febbraio M,Naseem KM

    更新日期:2020-03-01 00:00:00

  • Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

    abstract::Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive th...

    journal_title:Haematologica

    pub_type: 临床试验,杂志文章

    doi:10.3324/haematol.2015.132530

    authors: Narita A,Muramatsu H,Sekiya Y,Okuno Y,Sakaguchi H,Nishio N,Yoshida N,Wang X,Xu Y,Kawashima N,Doisaki S,Hama A,Takahashi Y,Kudo K,Moritake H,Kobayashi M,Kobayashi R,Ito E,Yabe H,Ohga S,Ohara A,Kojima S,Japan Ch

    更新日期:2015-12-01 00:00:00

  • The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A.

    abstract:BACKGROUND AND OBJECTIVES:The strongest risk factor identified for inhibitor development in people with severe hemophilia A is the type of factor VIII gene mutation. The objective of this study was to evaluate the mutation type dependent concordance rate of inhibitor formation in siblings. DESIGN AND METHODS:The gene ...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Astermark J,Oldenburg J,Escobar M,White GC 2nd,Berntorp E,Malmö International Brother Study study group.

    更新日期:2005-07-01 00:00:00

  • Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging.

    abstract:BACKGROUND:Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare th...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2009.019042

    authors: Pepe A,Meloni A,Capra M,Cianciulli P,Prossomariti L,Malaventura C,Putti MC,Lippi A,Romeo MA,Bisconte MG,Filosa A,Caruso V,Quarta A,Pitrolo L,Missere M,Midiri M,Rossi G,Positano V,Lombardi M,Maggio A

    更新日期:2011-01-01 00:00:00

  • Clonal stability of initial leukemia in a child with central nervous system relapse 7.4 years after bone marrow relapse of common acute lymphoblastic leukemic.

    abstract::Second central nervous system (CNS) relapses represent about 7.3% of subsequent recurrences of childhood acute lymphoblastic leukemia (ALL). In most children these subsequent CNS relapses occur during the first 18 months after diagnosis of the first relapse (mean 1.42 +/- 0.73 years). We present a patient who suffered...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Eckert C,Einsiedel HG,Hartmann R,von Stackelberg A,Völpel S,Guggemos A,Hanzsch N,Kawan L,Seeger K,Henze G

    更新日期:2004-07-01 00:00:00

  • Effect of interleukin-1beta and glutathione S-transferase genotypes on the development of gastric mucosa-associated lymphoid tissue lymphoma.

    abstract::e tested whether polymorphic variations in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and interleukin-1 (IL-1beta and IL-1RN) genes confer susceptibility to mucosa-associated lymphoid tissue lymphomas (MALT) in a Chinese population. The rates of GSTM1, GSTP1, IL-1beta and IL-1RN genotypes did not differ bet...

    journal_title:Haematologica

    pub_type: 信件

    doi:

    authors: Wu MS,Shun CT,Huang SP,Cheng AL,Chen LT,Lin JT

    更新日期:2004-08-01 00:00:00

  • Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors.

    abstract::T-cell acute lymphoblastic leukemia (T-ALL) patients frequently display NOTCH1 activating mutations and Notch can transcriptionally down-regulate the tumor suppressor PTEN. However, it is not clear whether NOTCH1 mutations associate with decreased PTEN expression in primary T-ALL. Here, we compared patients with or wi...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2009.011999

    authors: Silva A,Jotta PY,Silveira AB,Ribeiro D,Brandalise SR,Yunes JA,Barata JT

    更新日期:2010-04-01 00:00:00

  • Fludarabine in untreated and previously treated B-CLL patients: a report on efficacy and toxicity.

    abstract:BACKGROUND:It has been shown that fludarabine (FLU) is superior to conventional treatment in B-CLL for rate and quality of response, leading to CR even at the molecular level. In this paper we report our preliminary results with this drug in B-CLL patients. METHODS AND PATIENTS:Twenty-seven B-CLL patients (16 refracto...

    journal_title:Haematologica

    pub_type: 临床试验,杂志文章

    doi:

    authors: Spriano M,Clavio M,Carrara P,Canepa L,Miglino M,Pierri I,Celesti L,Rossi E,Vimercati R,Bruni R

    更新日期:1994-05-01 00:00:00

  • Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure.

    abstract::The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate t...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2019.233874

    authors: Robach P,Gammella E,Recalcati S,Girelli D,Castagna A,Roustit M,Lundby C,Lundby AK,Bouzat P,Vergès S,Séchaud G,Banco P,Uhr M,Cornu C,Sallet P,Cairo G

    更新日期:2021-02-01 00:00:00

  • HTLV-I positive adult T-cell leukaemia-lymphoma: report of a typical case from Italy.

    abstract::A case of acute adult T-cell leukemia-lymphoma (ATLL) was observed in northeast Italy, presenting with fever, lymphadenomegaly, splenomegaly, hypercalcemia and renal failure. Leukaemic cells were morphologically typical, expressed a T-cell CD4+ phenotype, did not display any helper functions, and grew in vitro under s...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Fanin R,Minutillo S,D'Agaro P,Raspadori D,Tassinari A,Tazzari P,Testoni N,Damiani D,Gallizia C,Michieli M

    更新日期:1990-07-01 00:00:00

  • Microenvironmental contributions to hematopoietic stem cell aging.

    abstract::Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process, which is the focus of another review in the same issue of Haematologica However, studies on the microenvironment that maintains and regulates HSC (HSC niche) over the past 20 years have suggested that microenvironme...

    journal_title:Haematologica

    pub_type: 杂志文章,评审

    doi:10.3324/haematol.2018.211334

    authors: Ho YH,Méndez-Ferrer S

    更新日期:2020-01-01 00:00:00

  • Feasibility and results of autologous stem cell transplantation in de novo acute myeloid leukemia in patients over 60 years old. Results of the CETLAM AML-99 protocol.

    abstract:BACKGROUND AND OBJECTIVES:The benefits of high-dose cytarabine, anthracyclines and hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia (AML) are greater in younger rather than in older patients. We assessed the proportion of patients over 60 years with de novo AML who qualified for intens...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Oriol A,Ribera JM,Esteve J,Guàrdia R,Brunet S,Bueno J,Pedro C,Llorente A,Tormo M,Besalduch J,Sánchez JM,Batlle M,Vivancos P,Carreras E,Vilà JM,Julià A,Sierra J,Montserrat E,Feliu E,CETLAM AML-99.

    更新日期:2004-07-01 00:00:00

  • A genetic score for the prediction of beta-thalassemia severity.

    abstract::Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We chara...

    journal_title:Haematologica

    pub_type: 杂志文章,多中心研究

    doi:10.3324/haematol.2014.113886

    authors: Danjou F,Francavilla M,Anni F,Satta S,Demartis FR,Perseu L,Manca M,Sollaino MC,Manunza L,Mereu E,Marceddu G,Pissard S,Joly P,Thuret I,Origa R,Borg J,Forni GL,Piga A,Lai ME,Badens C,Moi P,Galanello R

    更新日期:2015-04-01 00:00:00

  • CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting.

    abstract::Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we p...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2017.169946

    authors: Landberg N,von Palffy S,Askmyr M,Lilljebjörn H,Sandén C,Rissler M,Mustjoki S,Hjorth-Hansen H,Richter J,Ågerstam H,Järås M,Fioretos T

    更新日期:2018-03-01 00:00:00

  • Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis.

    abstract::Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated b...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2018.192898

    authors: Al-Sharea A,Lee MKS,Whillas A,Michell DL,Shihata WA,Nicholls AJ,Cooney OD,Kraakman MJ,Veiga CB,Jefferis AM,Jackson K,Nagareddy PR,Lambert G,Wong CHY,Andrews KL,Head GA,Chin-Dusting J,Murphy AJ

    更新日期:2019-03-01 00:00:00

  • Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis.

    abstract::The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic fe...

    journal_title:Haematologica

    pub_type: 杂志文章,评审

    doi:

    authors: Esteve J,Cervantes F,Rives S,Rozman M,Zarco MA,Montserrat E

    更新日期:1997-09-01 00:00:00

  • MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation.

    abstract::MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylati...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2012.070664

    authors: Pigazzi M,Manara E,Bresolin S,Tregnago C,Beghin A,Baron E,Giarin E,Cho EC,Masetti R,Rao DS,Sakamoto KM,Basso G

    更新日期:2013-04-01 00:00:00

  • Modulatory effects of mycobacterial heat-shock protein 70 in DNA vaccination against lymphoma.

    abstract:BACKGROUND AND OBJECTIVES:Pathogen-derived molecules are danger signals and are able to activate innate immunity that in turn controls and regulates generation of adaptive immune responses. Mycobacterium tuberculosis heat shock protein 70 (myc HSP70) has been shown to exert a potent adjuvant effect in vaccination again...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Liso A,Benedetti R,Fagioli M,Mariano A,Falini B

    更新日期:2005-01-01 00:00:00

  • Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.

    abstract::We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2019.238675

    authors: Svoboda J,Bair SM,Landsburg DJ,Nasta SD,Nagle SJ,Barta SK,Khan N,Filicko-O'Hara J,Gaballa S,Strelec L,Chong E,Mitnick S,Waite TS,King C,Ballard H,Youngman M,Gerson J,Plastaras JP,Maity A,Bogusz AM,Hung SS,Nakamu

    更新日期:2020-05-15 00:00:00

  • Cell type specific novel lncRNAs and circRNAs in the BLUEPRINT haematopoietic transcriptomes atlas.

    abstract::Transcriptional profiling of hematopoietic cell subpopulations has helped characterize the developmental stages of the hematopoietic system and the molecular bases of malignant and non-malignant blood diseases for the past three decades. Previously, only the genes targeted by expression microarrays could be profiled g...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2019.238147

    authors: Grassi L,Izuogu OG,Jorge NA,Seyres D,Bustamante M,Burden F,Farrow S,Farahi N,Martin FJ,Frankish A,Mudge JM,Kostadima M,Petersen R,Lambourne JJ,Rowlston S,Martin-Rendon E,Clarke L,Downes K,Estivill X,Flicek P,Marte

    更新日期:2020-07-23 00:00:00

  • Study of hemostasis in pediatric patients with portal vein thrombosis.

    abstract::We describe the behavior of hemostatic variables in children with portal vein thrombosis (PVT) and in a control pediatric population. Hereditary protein C (PC) or protein S (PS) deficiency was not a etiologic factor for PVT in children. Minor signs of consumption of coagulation factors II, V, fibrinogen and hyperfibri...

    journal_title:Haematologica

    pub_type: 信件

    doi:

    authors: Seixas CA,Hessel G,Siqueira LH,Machado TF,Gallizoni AM,Annichino-Bizzacchi JM

    更新日期:1998-10-01 00:00:00

  • The putative role of transforming viruses in childhood acute lymphoblastic leukemia.

    abstract::Epidemiological evidence suggests that infection is involved in the etiology of common acute lymphoblastic leukemia, either by stimulating an inappropriate immune response or in the form of a classical transforming agent. In an attempt to elucidate the role that infection is playing in this disease, we used representa...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: MacKenzie J,Greaves MF,Eden TO,Clayton RA,Perry J,Wilson KS,Jarrett RF

    更新日期:2006-02-01 00:00:00

  • Bone marrow transplantation for severe aplastic anemia: the Barcelona Hospital Clinic experience.

    abstract:BACKGROUND AND OBJECTIVE:The outcome of patients with severe aplastic anemia (SAA) has improved considerably over the last decades. Bone marrow transplantation (BMT) is the treatment of choice in young patients who have an HLA-identical sibling donor. This study analyzes the outcome and factors related to survival in p...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Hernández-Boluda JC,Marín P,Carreras E,Aguilar JL,Grañena A,Rozman C,Montserrat E

    更新日期:1999-01-01 00:00:00

  • Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor.

    abstract:BACKGROUND AND OBJECTIVES:Our objective was to improve the outcome of cord blood (CB) transplantation in adults, by overcoming the limitations imposed by the low number of stem cells present in CB units. DESIGN AND METHODS:We combined single CB units and co-infusion of third party donor (TPD)-derived peripheral blood ...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Magro E,Regidor C,Cabrera R,Sanjuán I,Forès R,Garcia-Marco JA,Ruiz E,Gil S,Bautista G,Millán I,Madrigal A,Fernandez MN

    更新日期:2006-05-01 00:00:00

  • Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines.

    abstract::We report an increased incidence of high relapse risk features in 157 APL Brazilian patients. Out of 134 patients treated with ATRA and anthracyclines, only 91 (67.9%) achieved remission because 43 (32%) died during induction. The death rate during consolidation was 10.5%. Bleeding complications were the most frequent...

    journal_title:Haematologica

    pub_type: 信件

    doi:10.3324/haematol.10874

    authors: Jácomo RH,Melo RA,Souto FR,de Mattos ER,de Oliveira CT,Fagundes EM,Bittencourt HN,Bittencourt RI,Bortolheiro TC,Paton EJ,Bendlin R,Ismael S,Chauffaille Mde L,Silva D,Pagnano KB,Ribeiro R,Rego EM

    更新日期:2007-10-01 00:00:00

  • The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women.

    abstract::Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. In nonanemic Taiwanese women (n=79, 44 TT variant, 35 CC variant), we administered standardized rice-based test meals containing 4 mg of labeled 57Fe or 58Fe a...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2020.264556

    authors: Buerkli S,Pei SN,Hsiao SC,Lee CT,Zeder C,Zimmermann MB,Moretti D

    更新日期:2020-10-05 00:00:00