Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response.


:The molecular basis of different outcomes in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionizing radiation (IR)-induced DNA double-strand breaks in 74 pediatric patients with ALL. We found an apoptosis-resistant response in 36% of patients characterized by failure to cleave caspase-3, -7, -9, and PARP1 by 24 hours after IR and an apoptosis-sensitive response with the cleavage of the same substrates in the remaining 64% of leukemias. Resistance to IR in vitro was associated with poor early blast clearance at day 7 or 15 and persistent minimal residual disease (MRD) at day 28 of induction treatment. Global gene expression profiling revealed abnormal up-regulation of multiple prosurvival pathways in response to IR in apoptosis-resistant leukemias and differential posttranscriptional activation of the PI3-Akt pathway was observed in representative resistant cases. Importantly, pharmacologic inhibition of selected prosurvival pathways sensitized apoptosis-resistant ALL cells to IR in vitro. We suggest that abnormal prosurvival responses to DNA damage provide one of the mechanisms of primary resistance in ALL, and that they should be considered as therapeutic targets in children with aggressive disease.






Marston E,Weston V,Jesson J,Maina E,McConville C,Agathanggelou A,Skowronska A,Mapp K,Sameith K,Powell JE,Lawson S,Kearns P,Falciani F,Taylor M,Stankovic T




Has Abstract


2009-01-01 00:00:00
















  • Rabbit and rat platelets do not respond to thrombin receptor peptides that activate human platelets.

    abstract::Human platelets are aggregated and induced to release their granule contents and form thromboxane by peptides as short as 6-amino acid residues (SFLLRN) corresponding to the newly released N-terminus of the thrombin receptor that is cleaved by thrombin. Using washed platelets, we found that these responses to SFLLRN (...


    pub_type: 杂志文章


    authors: Kinlough-Rathbone RL,Rand ML,Packham MA

    更新日期:1993-07-01 00:00:00

  • miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells.

    abstract::The recent discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation, affecting the immune system. Here, we identify their roles in regulating human plasmacytoid dendritic cell (PDC) activation. miRNA profiling showed the significantly differential expression of 19 miRNAs in PDCs after Tol...


    pub_type: 杂志文章


    authors: Zhou H,Huang X,Cui H,Luo X,Tang Y,Chen S,Wu L,Shen N

    更新日期:2010-12-23 00:00:00

  • High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation.

    abstract::In lymphatic tissues, chronic lymphocytic leukemia (CLL) cells are interspersed with CD68(+) nurselike cells (NLCs), T cells, and other stromal cells that constitute the leukemia microenvironment. However, the mechanism regulating colocalization of CLL and these accessory cells are largely unknown. To dissect the mole...


    pub_type: 杂志文章


    authors: Burger JA,Quiroga MP,Hartmann E,Bürkle A,Wierda WG,Keating MJ,Rosenwald A

    更新日期:2009-03-26 00:00:00

  • Antibody-induced intracellular signaling works in combination with radiation to eradicate lymphoma in radioimmunotherapy.

    abstract::Radioimmunotherapy (RIT) has emerged as an effective treatment for lymphoma, however the underlying mechanisms are poorly understood. We therefore investigated the relative contributions of antibody and targeted radiation to the clearance of tumor in vivo, using 2 different syngeneic murine B-cell lymphoma models. Alt...


    pub_type: 杂志文章


    authors: Du Y,Honeychurch J,Cragg MS,Bayne M,Glennie MJ,Johnson PW,Illidge TM

    更新日期:2004-02-15 00:00:00

  • Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells.

    abstract::We recently defined a critical role for p53 in regulating the quiescence of adult hematopoietic stem cells (HSCs) and identified necdin as a candidate p53 target gene. Necdin is a growth-suppressing protein and the gene encoding it is one of several that are deleted in patients with Prader-Willi syndrome. To define th...


    pub_type: 杂志文章


    authors: Asai T,Liu Y,Di Giandomenico S,Bae N,Ndiaye-Lobry D,Deblasio A,Menendez S,Antipin Y,Reva B,Wevrick R,Nimer SD

    更新日期:2012-08-23 00:00:00

  • The reversible binding of vinblastine to platelets: implications for therapy.

    abstract::The ability of platelets to adsorb vinblastine has been used to treat patients with immune thrombocytopenia. It is hypothesized that the drug-platelet complex is coated with antibody, taken up by macrophages which are then destroyed by the drug. We gave 16 courses of vinblastine-platelets to six patients with immune t...


    pub_type: 杂志文章


    authors: Kelton JG,McDonald JW,Barr RM,Walker I,Nicholson W,Neame PB,Hamid C,Wong TY,Hirsh J

    更新日期:1981-03-01 00:00:00

  • Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation.

    abstract::Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apop...


    pub_type: 杂志文章


    authors: Schmidt J,Ramis-Zaldivar JE,Nadeu F,Gonzalez-Farre B,Navarro A,Egan C,Montes-Mojarro IA,Marafioti T,Cabeçadas J,van der Walt J,Dojcinov S,Rosenwald A,Ott G,Bonzheim I,Fend F,Campo E,Jaffe ES,Salaverria I,Quintanilla-M

    更新日期:2017-07-20 00:00:00

  • Clonal evolution in atypical chronic granulocytic leukemia: a non-Philadelphia translocation.

    abstract::Hemopoietic cells in chronic granulocytic leukemia (CGL) frequently contain a chromosome translocation involving chromosome 22 and another autosome, usually number 9. The translocated chromosome 22 is known as the Philadelphia (Ph) chromosome. The appearance of a second Ph chromosome is the most common cytogenetic abn...


    pub_type: 杂志文章


    authors: Bagby GC Jr,Kaiser-McCaw B,Hecht F,Koler RD,Linman JW

    更新日期:1978-06-01 00:00:00

  • Cellular therapies for graft-versus-host disease: a tale of tissue repair and tolerance.

    abstract::The success of allogeneic hematopoietic cell transplantation depends heavily on the delicate balance between the activity of the donor immune system against malignant and nonmalignant cells of the recipient. Abrogation of alloreactivity will lead to disease relapse, whereas untamed allo-immune responses will lead to l...


    pub_type: 杂志文章


    authors: Voermans C,Hazenberg MD

    更新日期:2020-07-23 00:00:00

  • Posttranslational processing of a human myeloid lysosomal protein, myeloperoxidase.

    abstract::Myeloperoxidase (MPO) is a lysosomal enzyme present in the azurophilic granules of human neutrophils and monocytes and is important for optimal oxygen-dependent killing of microorganisms. The native molecule is a heterodimer composed of a pair of heavy-light protomers, each containing a 59-kDa and 13.5-kDa subunit. Th...


    pub_type: 杂志文章


    authors: Nauseef WM

    更新日期:1987-10-01 00:00:00

  • Detection of cytarabine resistance in patients with acute myelogenous leukemia using flow cytometry.

    abstract::Cytarabine (Ara-C) is currently used in the treatment of adult acute myeloid leukemia (AML). To predict the results of induction chemotherapy, it could be useful to detect leukemic cells that are resistant to Ara-C in patients with AML. Using a bromodeoxyuridine/DNA (BrdUrd/DNA) staining method in flow cytometry (FCM)...


    pub_type: 杂志文章


    authors: Lacombe F,Belloc F,Dumain P,Puntous M,Makhoul PC,Saux MC,Bernard P,Boisseau MR,Reiffers J

    更新日期:1994-08-01 00:00:00

  • G protein subunit G alpha 16 expression is restricted to progenitor B cells during human B-cell differentiation.

    abstract::Recently G alpha 16, a new guanosine triphosphate (GTP) binding protein alpha subunit has been described to be specifically expressed in human hematopoietic cells. Expression of G alpha 16 was observed in human cell lines of myelomonocytic and T-lymphocytic origin, but not in human B-cell lines Raji and IM9. We studie...


    pub_type: 杂志文章


    authors: Mapara MY,Bommert K,Bargou RC,Leng C,Beck C,Ludwig WD,Gierschik P,Dörken B

    更新日期:1995-04-01 00:00:00

  • Rh blood group-specific antibodies in immune hemolytic anemia induced by nomifensine.

    abstract::Nomifensine (Merital, Alival; Hoechst, Frankfurt, FRG), an antidepressant drug, may cause immune hemolytic anemia (IHA) of the so-called immune complex type that is believed to occur by means of an innocent-bystander mechanism. In this report we describe findings that are not consistent with this mechanism in a patien...


    pub_type: 杂志文章


    authors: Salama A,Mueller-Eckhardt C

    更新日期:1986-12-01 00:00:00

  • Activation of the human immunodeficiency virus-1 long terminal repeat by respiratory burst oxidants of neutrophils.

    abstract::The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) introduced in association with the luciferase reporter gene into Jurkat T cells was strongly activated by a combination of human neutrophils and phorbol myristate acetate (PMA). Activation was not observed when normal neutrophils were replaced ...


    pub_type: 杂志文章


    authors: Klebanoff SJ,Headley CM

    更新日期:1999-01-01 00:00:00

  • Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.

    abstract::The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cel...


    pub_type: 杂志文章


    authors: Hipp MM,Hilf N,Walter S,Werth D,Brauer KM,Radsak MP,Weinschenk T,Singh-Jasuja H,Brossart P

    更新日期:2008-06-15 00:00:00

  • Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.

    abstract::Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssR...


    pub_type: 杂志文章


    authors: Phipps S,Lam CE,Mahalingam S,Newhouse M,Ramirez R,Rosenberg HF,Foster PS,Matthaei KI

    更新日期:2007-09-01 00:00:00

  • Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase.

    abstract::Interleukin 2 (IL-2) rescued human natural killer (NK) KHYG-1 cells from apoptosis along with a reduction of ceramide. Conversely, an increase of ceramide inhibited IL-2-rescued survival. IL-2 deprivation-induced activation of acid sphingomyelinase (SMase) and inhibition of glucosylceramide synthase (GCS) and sphingom...


    pub_type: 杂志文章


    authors: Taguchi Y,Kondo T,Watanabe M,Miyaji M,Umehara H,Kozutsumi Y,Okazaki T

    更新日期:2004-11-15 00:00:00

  • Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin.

    abstract::Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cel...


    pub_type: 杂志文章


    authors: Lin L,Goldberg YP,Ganz T

    更新日期:2005-10-15 00:00:00

  • CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions.

    abstract::The number of neutrophils in the blood is tightly regulated to ensure adequate protection against microbial pathogens while minimizing damage to host tissue. Neutrophil homeostasis in the blood is achieved through a balance of neutrophil production, release from the bone marrow, and clearance from the circulation. Acc...


    pub_type: 杂志文章


    authors: Eash KJ,Means JM,White DW,Link DC

    更新日期:2009-05-07 00:00:00

  • Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial.

    abstract::Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eli...


    pub_type: 杂志文章,多中心研究


    authors: Alvarnas JC,Le Rademacher J,Wang Y,Little RF,Akpek G,Ayala E,Devine S,Baiocchi R,Lozanski G,Kaplan L,Noy A,Popat U,Hsu J,Morris LE Jr,Thompson J,Horowitz MM,Mendizabal A,Levine A,Krishnan A,Forman SJ,Navarro WH,

    更新日期:2016-08-25 00:00:00

  • Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.

    abstract::Perforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice defi...


    pub_type: 杂志文章


    authors: Street SE,Cretney E,Smyth MJ

    更新日期:2001-01-01 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...


    pub_type: 杂志文章


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

    更新日期:2005-11-15 00:00:00

  • Coexistence of multiple mechanisms of PT523 resistance in human leukemia cells harboring 3 reduced folate carrier alleles: transcriptional silencing, inactivating mutations, and allele loss.

    abstract::The reduced folate carrier (RFC) is the dominant route for the uptake of various antifolates including PT523, a potent dihydrofolate reductase inhibitor (Ki = 0.35 pM) and an excellent transport substrate of the RFC (Kt = 0.7 microM). Here, we describe the multiple mechanisms of RFC inactivation in human leukemia PT52...


    pub_type: 杂志文章


    authors: Kaufman Y,Ifergan I,Rothem L,Jansen G,Assaraf YG

    更新日期:2006-04-15 00:00:00

  • Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors.

    abstract::Distinct human dendritic cell (DC) subsets differentially control immunity. Thus, insights into their in vivo functions are important to understand the launching and modulation of immune responses. We show that nonobese diabetic/LtSz-scid/scid (NOD/SCID) mice engrafted with human CD34+ hematopoietic progenitors develo...


    pub_type: 杂志文章


    authors: Palucka AK,Gatlin J,Blanck JP,Melkus MW,Clayton S,Ueno H,Kraus ET,Cravens P,Bennett L,Padgett-Thomas A,Marches F,Islas-Ohlmayer M,Garcia JV,Banchereau J

    更新日期:2003-11-01 00:00:00

  • Long-awaited news for hepatic veno-occlusive disease.

    abstract::In this issue of Blood, Palomo et al provide new insight into the mechanism of action of defibrotide as an endothelial protective agent, while Richardson et al present the encouraging final results of the phase 3 clinical study of defibrotide for the treatment of severe hepatic veno-occlusive disease (VOD), showing a ...


    pub_type: 评论,杂志文章


    authors: Arai S

    更新日期:2016-03-31 00:00:00

  • Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma.

    abstract::Chromosomal rearrangements affecting RUNX1 and CBFB are common in acute leukemias. These mutations result in the expression of fusion proteins that act dominant-negatively to suppress the normal function of the Runt-related transcription factor 1 (RUNX)/core binding factor beta (CBFbeta) complexes. In addition, loss-o...


    pub_type: 杂志文章


    authors: Kundu M,Compton S,Garrett-Beal L,Stacy T,Starost MF,Eckhaus M,Speck NA,Liu PP

    更新日期:2005-11-15 00:00:00

  • Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency.

    abstract::Fibrillar collagens are among the most potent activators of platelets and play an important role in the initiation of thrombosis. The glycoprotein VI (GPVI)/FcRgamma-chain complex is a central collagen receptor and inhibitors of GPVI produce a major defect in arterial thrombogenesis. In this study we have examined art...


    pub_type: 杂志文章


    authors: Mangin P,Yap CL,Nonne C,Sturgeon SA,Goncalves I,Yuan Y,Schoenwaelder SM,Wright CE,Lanza F,Jackson SP

    更新日期:2006-06-01 00:00:00

  • Putative oncogenic role of the erythropoietin receptor in murine and human erythroleukemia cells.

    abstract::To determine whether the erythropoietin receptor (Epo-R) plays a role in the course of malignant erythropoietic disorders, this gene was studied in murine and human erythroleukemia cells. An altered Epo-R gene was found in a murine Friend erythroleukemia cell line, FCL1, due to a spleen focus-forming virus (SFFV) long...


    pub_type: 杂志文章


    authors: Chretien S,Moreau-Gachelin F,Apiou F,Courtois G,Mayeux P,Dutrillaux B,Cartron JP,Gisselbrecht S,Lacombe C

    更新日期:1994-04-01 00:00:00

  • AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model.

    abstract::As acute myeloid leukemia (AML) xenograft models improve, the potential for using them to evaluate novel therapeutic strategies becomes more appealing. Currently, there is little information on using standard chemotherapy regimens in AML xenografts. Here we have characterized the immunodeficient mouse response to comb...


    pub_type: 杂志文章


    authors: Wunderlich M,Mizukawa B,Chou FS,Sexton C,Shrestha M,Saunthararajah Y,Mulloy JC

    更新日期:2013-03-21 00:00:00

  • Hertwig's anemia: characterization of the stem cell defect.

    abstract::Mice homozygous for Hertwig's anemia, an/an, have a mild macrocytic anemia and are refractory to the potentially curative action of exogenously administered erythropoietin (EP). Both red and white blood cell numbers are decreased. One possible explanation is that a precursor stem cell population is in short supply. We...


    pub_type: 杂志文章


    authors: Barker JE,Bernstein SE

    更新日期:1983-04-01 00:00:00