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1. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2020

2. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2019

4. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Author

Larson, RA, Mandrekar, SJ, Huebner, LJ, Sanford, BL, Laumann, K, Geyer, S, Bloomfield, CD, Thiede, C, Prior, TW, Dohner, K, Marcucci, G, Voso, MT, Klisovic, RB, Galinsky, I, Wei, AH, Sierra, J, Sanz, MA, Brandwein, JM, de Witte, T, Niederwieser, D, Appelbaum, FR, Medeiros, BC, Tallman, MS, Krauter, J, Schlenk, RF, Ganser, A, Serve, H, Ehninger, G, Amadori, S, Gathmann, I, Dohner, H, Stone, RM, Larson, RA, Mandrekar, SJ, Huebner, LJ, Sanford, BL, Laumann, K, Geyer, S, Bloomfield, CD, Thiede, C, Prior, TW, Dohner, K, Marcucci, G, Voso, MT, Klisovic, RB, Galinsky, I, Wei, AH, Sierra, J, Sanz, MA, Brandwein, JM, de Witte, T, Niederwieser, D, Appelbaum, FR, Medeiros, BC, Tallman, MS, Krauter, J, Schlenk, RF, Ganser, A, Serve, H, Ehninger, G, Amadori, S, Gathmann, I, Dohner, H, and Stone, RM

Abstract

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

Published
2021

5. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, and Lo-Coco, F

Subjects
Hematology
Published
2019

6. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Author

Dohner, K., Thiede, C., Jahn, N., Panina, E., Gambietz, A., Larson, R.A., Prior, T.W., Marcucci, G., Jones, Dan, Krauter, J., Heuser, M., Voso, M.T., Ottone, T., Nomdedeu, J.F., Mandrekar, S.J., Klisovic, R.B., Wei, A.H., Sierra, J., Sanz, Mariano, Brandwein, J.M., Witte, T.J. de, Jansen, J.H., Niederwieser, D., Appelbaum, F.R., Medeiros, B.C., Tallman, M.S., Schlenk, R.F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Gathmann, I., Benner, A., Pallaud, C., Stone, R.M., Dohner, H., Bloomfield, C.D., Dohner, K., Thiede, C., Jahn, N., Panina, E., Gambietz, A., Larson, R.A., Prior, T.W., Marcucci, G., Jones, Dan, Krauter, J., Heuser, M., Voso, M.T., Ottone, T., Nomdedeu, J.F., Mandrekar, S.J., Klisovic, R.B., Wei, A.H., Sierra, J., Sanz, Mariano, Brandwein, J.M., Witte, T.J. de, Jansen, J.H., Niederwieser, D., Appelbaum, F.R., Medeiros, B.C., Tallman, M.S., Schlenk, R.F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Gathmann, I., Benner, A., Pallaud, C., Stone, R.M., Dohner, H., and Bloomfield, C.D.

Abstract

Contains fulltext : 218279.pdf (Publisher’s version ) (Open Access), Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (>/=0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Published
2020

10. Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia

Author

Bhayadia, R, Krowiorz, K, Haetscher, N, Jammal, R, Emmrich, S, Obulkasim, Askar, Fiedler, J, Schwarzer, A, Rouhi, A, Heuser, M, Wingert, S, Bothur, S, Dohner, K, Matzig, T, Ng, M, Reinhardt, D, Dohner, H, Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Heckl, D, Fornerod, M.W.J., Thum, T, Humphries, RK, Rieger, MA, Kuchenbauer, F, Klusmann, JH, Bhayadia, R, Krowiorz, K, Haetscher, N, Jammal, R, Emmrich, S, Obulkasim, Askar, Fiedler, J, Schwarzer, A, Rouhi, A, Heuser, M, Wingert, S, Bothur, S, Dohner, K, Matzig, T, Ng, M, Reinhardt, D, Dohner, H, Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Heckl, D, Fornerod, M.W.J., Thum, T, Humphries, RK, Rieger, MA, Kuchenbauer, F, and Klusmann, JH

Published
2018

12. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation

Author

Stone, R.M., Mandrekar, S.J., Sanford, B.L., Laumann, K., Geyer, S., Bloomfield, C.D., Thiede, C., Prior, T.W., Dohner, K., Marcucci, G., Lo-Coco, F., Klisovic, R.B., Wei, A., Sierra, J., Sanz, M.A., Brandwein, J.M., Witte, T.J. de, Niederwieser, D., Appelbaum, F.R., Medeiros, B.C., Tallman, M.S., Krauter, J., Schlenk, R.F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Larson, R.A., Dohner, H., Stone, R.M., Mandrekar, S.J., Sanford, B.L., Laumann, K., Geyer, S., Bloomfield, C.D., Thiede, C., Prior, T.W., Dohner, K., Marcucci, G., Lo-Coco, F., Klisovic, R.B., Wei, A., Sierra, J., Sanz, M.A., Brandwein, J.M., Witte, T.J. de, Niederwieser, D., Appelbaum, F.R., Medeiros, B.C., Tallman, M.S., Krauter, J., Schlenk, R.F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Larson, R.A., and Dohner, H.

Abstract

Item does not contain fulltext, BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of mi

Published
2017

13. Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia

Author

Hirsch, S, Blatte, TJ, Grasedieck, S, Cocciardi, S, Rouhi, A, Jongen - Lavrencic, Mojca, Paschka, P, Kronke, J, Gaidzik, VI, Dohner, H, Schlenk, RF, Kuchenbauer, F, Dohner, K, Dolnik, A, Bullinger, L, Hirsch, S, Blatte, TJ, Grasedieck, S, Cocciardi, S, Rouhi, A, Jongen - Lavrencic, Mojca, Paschka, P, Kronke, J, Gaidzik, VI, Dohner, H, Schlenk, RF, Kuchenbauer, F, Dohner, K, Dolnik, A, and Bullinger, L

Published
2017

14. MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Author

Vegi, N.M., Klappacher, J., Oswald, F., Mulaw, M.A., Mandoli, A., Thiel, V.N., Bamezai, S., Feder, K., Martens, J.H.A., Rawat, V.P.S., Mandal, T., Quintanilla-Martinez, L., Spiekermann, K., Hiddemann, W., Dohner, K., Dohner, H., Stunnenberg, H.G., Feuring-Buske, M., Buske, C., Vegi, N.M., Klappacher, J., Oswald, F., Mulaw, M.A., Mandoli, A., Thiel, V.N., Bamezai, S., Feder, K., Martens, J.H.A., Rawat, V.P.S., Mandal, T., Quintanilla-Martinez, L., Spiekermann, K., Hiddemann, W., Dohner, K., Dohner, H., Stunnenberg, H.G., Feuring-Buske, M., and Buske, C.

Abstract

Contains fulltext : 159977.pdf (publisher's version ) (Open Access)

Published
2016

15. Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

Author

Hutter-Kronke, M.-L., primary, Benner, A., additional, Dohner, K., additional, Krauter, J., additional, Weber, D., additional, Moessner, M., additional, Kohne, C.-H., additional, Horst, H. A., additional, Schmidt-Wolf, I. G. H., additional, Rummel, M., additional, Gotze, K., additional, Koller, E., additional, Petzer, A. L., additional, Salwender, H., additional, Fiedler, W., additional, Kirchen, H., additional, Haase, D., additional, Kremers, S., additional, Theobald, M., additional, Matzdorff, A. C., additional, Ganser, A., additional, Dohner, H., additional, and Schlenk, R. F., additional

Published
2016
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16. Molecular Cytogenetic Characterization of a Critical Region in Bands 7q35-q36 Commonly Deleted in Malignant Myeloid Disorders

Author

Dohner, K., Brown, J., Hehmann, U., Hetzel, C., Stewart, J., Lowther, G., Scholl, C., Frohling, S., Cuneo, A., Tsui, Lc, Lichter, P., Stephen W. Scherer, and Dohner, H.

Subjects
Genetic Markers, Leukemia, Myeloid, hemic and lymphatic diseases, Immunology, Chromosome Mapping, Humans, Genes, Tumor Suppressor, Cell Biology, Hematology, Biochemistry, Chromosomes, Human, Pair 7, Sequence Deletion
Abstract

Loss of chromosome 7 (−7) or deletion of the long arm (7q−) are recurring chromosome abnormalities in myeloid leukemias. The association of −7/7q− with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS] , n = 3; de novo acute myeloid leukemia [AML], n = 9; therapy-related (t-) AML, n = 1) which, on chromosome banding analysis, exhibited deletions (n = 12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (−7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.

Published
1998
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17. Aml1-eto collaborates with the homeobox genes meis1 and meis2 in inducing aml

Author

Vegi, N.M., Klappacher, J., Oswald, F., Claus, R., Mulaw, M.A., Mandoli, A., Thiel, V., Martens, J.H.A., Rawat, V.P.S., Quintanilla-Fend, L., Plass, C., Dohner, K., Dohner, H., Hiddemann, W., Stunnenberg, H.G., Feuring-Buske, M., and Buske, C.

Subjects
Molecular Biology
Abstract

Item does not contain fulltext

Published
2013

19. PRIMARY MYELOFIBROSIS, POST-ET AND POST-PV MYELOFIBROSIS HAVE DISTINCT CLINICAL PROFILES AND SYMPTOMATIC BURDENS : AN ANALYSIS BY THE MPN QUALITY OF LIFE INTERNATIONAL STUDY GROUP (MPN-QOL ISG)

Author

Geyer, H., Kosiorek, H., Scherber, R., Dueck, A., Jean-Jacques, K., Xiao, Z., Zweegman, S., Sackman, F., Hernandez-Maraver, D., Dohner, K., Harrison, C., Radia, D., Muxi, P., Besses, C., Cervantes, F., Johansson, P., Andreasson, B., Rambaldi, A., Barbui, T., Vannucchi, A., Passamonti, F., Samuelsson, J., Birgegård, Gunnar, Bonatz, K., Reiter, A., Boyer, F., Etienne, G., Ianotto, J. -C, Ranta, D., Roy, L., Cahn, J. -Y, Maldonado, N., Barosi, G., Ferrari, M., Cannon, K., te Boekhorst, P. A. W., Klauke, K., Schouten, H., Pahl, H., Griesshammer, M., Stegelmann, F., Lehmann, T., Xu, Z., Zhang, Y., Sun, X., Xu, J., Zhang, P., Mesa, R., Geyer, H., Kosiorek, H., Scherber, R., Dueck, A., Jean-Jacques, K., Xiao, Z., Zweegman, S., Sackman, F., Hernandez-Maraver, D., Dohner, K., Harrison, C., Radia, D., Muxi, P., Besses, C., Cervantes, F., Johansson, P., Andreasson, B., Rambaldi, A., Barbui, T., Vannucchi, A., Passamonti, F., Samuelsson, J., Birgegård, Gunnar, Bonatz, K., Reiter, A., Boyer, F., Etienne, G., Ianotto, J. -C, Ranta, D., Roy, L., Cahn, J. -Y, Maldonado, N., Barosi, G., Ferrari, M., Cannon, K., te Boekhorst, P. A. W., Klauke, K., Schouten, H., Pahl, H., Griesshammer, M., Stegelmann, F., Lehmann, T., Xu, Z., Zhang, Y., Sun, X., Xu, J., Zhang, P., and Mesa, R.

Published
2015

20. STAT1 activation in association with JAK2 exon 12 mutations

Author

Godfrey, A. L., primary, Chen, E., additional, Massie, C. E., additional, Silber, Y., additional, Pagano, F., additional, Bellosillo, B., additional, Guglielmelli, P., additional, Harrison, C. N., additional, Reilly, J. T., additional, Stegelmann, F., additional, Bijou, F., additional, Lippert, E., additional, Boiron, J.-M., additional, Dohner, K., additional, Vannucchi, A. M., additional, Besses, C., additional, and Green, A. R., additional

Published
2015
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21. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia: A study of 6,515 cases of AML

Author

Groschel, S., Lugthart, S., Beverloo, B.H., Kayser, S., Valk, P.J., Van Zelderen-Bhola, S.L., Ossenkoppele, G.J., Vellenga, E., van den Berg-de Ruiter, E., Schanz, U., Verhoef, G., Ferrant, A, Kohne, C.H., Pfreundschuh, M., Horst, H.A., Koller, E., von Lilienfeld-Toal, M., Bentz, M., Ganser, A., Schlegelberger, B., Jotterand, M., Krauter, J., Pabst, T., Theobald, M, Schlenk, R.F., Delwel, R., Dohner, K., Lowenberg, B., Dohner, H., Hematology, and CCA - Innovative therapy

Published
2010

23. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group

Author

Paschka, P., primary, Schlenk, R. F., additional, Gaidzik, V. I., additional, Herzig, J. K., additional, Aulitzky, T., additional, Bullinger, L., additional, Spath, D., additional, Teleanu, V., additional, Kundgen, A., additional, Kohne, C.-H., additional, Brossart, P., additional, Held, G., additional, Horst, H.-A., additional, Ringhoffer, M., additional, Gotze, K., additional, Nachbaur, D., additional, Kindler, T., additional, Heuser, M., additional, Thol, F., additional, Ganser, A., additional, Dohner, H., additional, and Dohner, K., additional

Published
2015
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24. Gender Differences and MPN Symptom Burden : An Analysis by the MPN Quality of Life International Study Group (MPN-QOL ISG)

Author

Geyer, H., Emanuel, R., Dueck, A., Kiladjian, J. J., Xiao, Z., Slot, S., Zweegman, S., Sackman, F., Kerguelen Fuentes, A., Hernandez-Maraver, D., Dohner, K., Harrison, C., Radia, D., Muxi, P., Besses, C., Cervantes, F., Johansson, P., Andreasson, B., Rambaldi, A., Barbui, T., Vannucchi, A., Passamonti, F., Samuelsson, J., Birgegård, Gunnar, Bonatz, K., Reiter, A., Boyer, F., Etienne, G., Ianotto, J. C., Ranta, D., Roy, L., Cahn, J. Y., Maldonado, N., Barosi, G., Ferrari, M., Cannon, K., te Boekhorst, P. A., Klauke, K., Schouten, H., Pahl, H., Griesshammer, M., Stegelmann, F., Lehmann, T., Xu, Z., Zhang, Y., Sun, X., Xu, J., Zhang, P., Mesa, R., Geyer, H., Emanuel, R., Dueck, A., Kiladjian, J. J., Xiao, Z., Slot, S., Zweegman, S., Sackman, F., Kerguelen Fuentes, A., Hernandez-Maraver, D., Dohner, K., Harrison, C., Radia, D., Muxi, P., Besses, C., Cervantes, F., Johansson, P., Andreasson, B., Rambaldi, A., Barbui, T., Vannucchi, A., Passamonti, F., Samuelsson, J., Birgegård, Gunnar, Bonatz, K., Reiter, A., Boyer, F., Etienne, G., Ianotto, J. C., Ranta, D., Roy, L., Cahn, J. Y., Maldonado, N., Barosi, G., Ferrari, M., Cannon, K., te Boekhorst, P. A., Klauke, K., Schouten, H., Pahl, H., Griesshammer, M., Stegelmann, F., Lehmann, T., Xu, Z., Zhang, Y., Sun, X., Xu, J., Zhang, P., and Mesa, R.

Published
2014

25. Clinical and functional implications of microRNA mutations in a cohort of 935 patients with myelodysplastic syndromes and acute myeloid leukemia

Author

Thol, F., primary, Scherr, M., additional, Kirchner, A., additional, Shahswar, R., additional, Battmer, K., additional, Kade, S., additional, Chaturvedi, A., additional, Koenecke, C., additional, Stadler, M., additional, Platzbecker, U., additional, Thiede, C., additional, Schroeder, T., additional, Kobbe, G., additional, Bug, G., additional, Ottmann, O., additional, Hofmann, W.-K., additional, Kroger, N., additional, Fiedler, W., additional, Schlenk, R., additional, Dohner, K., additional, Dohner, H., additional, Krauter, J., additional, Eder, M., additional, Ganser, A., additional, and Heuser, M., additional

Published
2014
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27. Genome-wide genotyping of acute myeloid leukemia with translocation t(9;11)(p22;q23) reveals novel recurrent genomic alterations

Author

Kuhn, M. W. M., primary, Bullinger, L., additional, Groschel, S., additional, Kronke, J., additional, Edelmann, J., additional, Rucker, F. G., additional, Eiwen, K., additional, Paschka, P., additional, Gaidzik, V. I., additional, Holzmann, K., additional, Schlenk, R. F., additional, Dohner, H., additional, and Dohner, K., additional

Published
2014
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28. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2

Author

Jutzi, J.S., Bogeska, R., Nikoloski, G., Schmid, C.A., Seeger, T.S., Stegelmann, F., Schwemmers, S., Grunder, A., Peeken, J.C., Gothwal, M., Wehrle, J., Aumann, K., Hamdi, K., Dierks, C., Wang, W., Dohner, K., Jansen, J.H., Pahl, H.L., Jutzi, J.S., Bogeska, R., Nikoloski, G., Schmid, C.A., Seeger, T.S., Stegelmann, F., Schwemmers, S., Grunder, A., Peeken, J.C., Gothwal, M., Wehrle, J., Aumann, K., Hamdi, K., Dierks, C., Wang, W., Dohner, K., Jansen, J.H., and Pahl, H.L.

Abstract

Item does not contain fulltext, The molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of several different mutations in MPN patients. We have recently described overexpression of the transcription factor NF-E2 in MPN patients and shown that elevated NF-E2 levels in vivo cause an MPN phenotype and predispose to leukemic transformation in transgenic mice. We report the presence of acquired insertion and deletion mutations in the NF-E2 gene in MPN patients. These result in truncated NF-E2 proteins that enhance wild-type (WT) NF-E2 function and cause erythrocytosis and thrombocytosis in a murine model. NF-E2 mutant cells acquire a proliferative advantage, witnessed by clonal dominance over WT NF-E2 cells in MPN patients. Our data underscore the role of increased NF-E2 activity in the pathophysiology of MPNs.

Published
2013

29. High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9-positive patients

Author

Noordermeer, S.M., Sanders, M.P.A., Gilissen, C.F., Tonnissen, E., Heijden, A. van der, Dohner, K., Bullinger, L., Jansen, J.H., Valk, P.J., Reijden, B.A. van der, Noordermeer, S.M., Sanders, M.P.A., Gilissen, C.F., Tonnissen, E., Heijden, A. van der, Dohner, K., Bullinger, L., Jansen, J.H., Valk, P.J., and Reijden, B.A. van der

Abstract

Item does not contain fulltext, Aberrations in protein ubiquitination have recently been identified in the pathogenesis of acute myeloid leukemia (AML). We studied whether expression changes of more than 1600 ubiquitination related genes correlated with clinical outcome in 525 adult AML patients. High expression of one of these genes, BRE, was observed in 3% of the cases and predicted favorable prognosis independently of known prognostic factors (5-year overall survival: 57%). Remarkably, unsupervised expression profiling showed that 86% of high BRE-expressing patients were confined to a previously unrecognized cluster. High BRE expression was mutually exclusive with FLT3 ITD, CEBPA, IDH1, and IDH2 mutations, EVI1 overexpression, and favorable karyotypes. In contrast, high BRE expression co-occurred strongly with FAB M5 morphology and MLL-AF9 fusions. Within the group of MLL-AF9-positive patients, high BRE expression predicted superior survival, while normal BRE expression predicted extremely poor survival (5-year overall survival of 80% vs 0%, respectively, P = .0002). Both the co-occurrence of high BRE expression with MLL-AF9 and its prognostic impact were confirmed in an independent cohort of 436 AML patients. Thus, high BRE expression defines a novel subtype of adult AML characterized by a favorable prognosis. This work contributes to improved risk stratification in AML, especially among MLL-AF9-positive patients.

Published
2011

30. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Author

Liso, A, Castiglione, F, Cappuccio, A, Stracci, F, Schlenk, RF, Amadori, S, Thiede, C, Schnittger, S, Valk, Peter, Dohner, K, Martelli, MF, Schaich, M, Krauter, J, Ganser, A, Martelli, MP, Bolli, N, Löwenberg, Bob, Haferlach, T, Ehninger, G, Mandelli, F, Dohner, H, Michor, F, Falini, B, Liso, A, Castiglione, F, Cappuccio, A, Stracci, F, Schlenk, RF, Amadori, S, Thiede, C, Schnittger, S, Valk, Peter, Dohner, K, Martelli, MF, Schaich, M, Krauter, J, Ganser, A, Martelli, MP, Bolli, N, Löwenberg, Bob, Haferlach, T, Ehninger, G, Mandelli, F, Dohner, H, Michor, F, and Falini, B

Abstract

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.

Published
2008

31. RBC-transfusion guidelines update

Author

Gale, R.P., primary, Barosi, G., additional, Barbui, T., additional, Cervantes, F., additional, Dohner, K., additional, Dupriez, B., additional, Gupta, V., additional, Harrison, C., additional, Hoffman, R., additional, Kiladjian, J.J., additional, Mesa, R., additional, Mc Mullin, M.F., additional, Passamonti, F., additional, Ribrag, V., additional, Roboz, G., additional, Saglio, G., additional, Vannucchi, A., additional, and Verstovsek, S., additional

Published
2012
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32. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Author

Lubbert, M., primary, Ruter, B. H., additional, Claus, R., additional, Schmoor, C., additional, Schmid, M., additional, Germing, U., additional, Kuendgen, A., additional, Rethwisch, V., additional, Ganser, A., additional, Platzbecker, U., additional, Galm, O., additional, Brugger, W., additional, Heil, G., additional, Hackanson, B., additional, Deschler, B., additional, Dohner, K., additional, Hagemeijer, A., additional, Wijermans, P. W., additional, and Dohner, H., additional

Published
2011
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33. Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

Author

Russ, A. C., primary, Sander, S., additional, Luck, S. C., additional, Lang, K. M., additional, Bauer, M., additional, Rucker, F. G., additional, Kestler, H. A., additional, Schlenk, R. F., additional, Dohner, H., additional, Holzmann, K., additional, Dohner, K., additional, and Bullinger, L., additional

Published
2011
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36. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Author

Liso, A., primary, Castiglione, F., additional, Cappuccio, A., additional, Stracci, F., additional, Schlenk, R. F., additional, Amadori, S., additional, Thiede, C., additional, Schnittger, S., additional, Valk, P. J.M., additional, Dohner, K., additional, Martelli, M. F., additional, Schaich, M., additional, Krauter, J., additional, Ganser, A., additional, Martelli, M. P., additional, Bolli, N., additional, Lowenberg, B., additional, Haferlach, T., additional, Ehninger, G., additional, Mandelli, F., additional, Dohner, H., additional, Michor, F., additional, and Falini, B., additional

Published
2008
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39. SEURAT: Visual analytics for the integrated analysis of microarray data

Author

Bullinger Lars, Döhner Konstanze, Rücker Frank, Lück Sonja, Sill Martin, Gribov Alexander, Benner Axel, and Unwin Antony

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background In translational cancer research, gene expression data is collected together with clinical data and genomic data arising from other chip based high throughput technologies. Software tools for the joint analysis of such high dimensional data sets together with clinical data are required. Results We have developed an open source software tool which provides interactive visualization capability for the integrated analysis of high-dimensional gene expression data together with associated clinical data, array CGH data and SNP array data. The different data types are organized by a comprehensive data manager. Interactive tools are provided for all graphics: heatmaps, dendrograms, barcharts, histograms, eventcharts and a chromosome browser, which displays genetic variations along the genome. All graphics are dynamic and fully linked so that any object selected in a graphic will be highlighted in all other graphics. For exploratory data analysis the software provides unsupervised data analytics like clustering, seriation algorithms and biclustering algorithms. Conclusions The SEURAT software meets the growing needs of researchers to perform joint analysis of gene expression, genomical and clinical data.

Published
2010
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40. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial

Author

Marco Sborgia, Marco Vignetti, Massimo Breccia, Fabio Efficace, Roberto Cairoli, Hartmut Link, Uwe Platzbecker, Norbert Schmitz, Ombretta Annibali, Agostino Cortelezzi, Francesca Paoloni, Eros Di Bona, Nicola Di Renzo, Alfonso Maria D'Arco, Lorella Melillo, Francesco Lo-Coco, Peter Brossart, Felicetto Ferrara, Chiara Frairia, Franco Mandelli, Christoph Röllig, Laura Cicconi, Claudio Fozza, Konstanze Döhner, Walter Fiedler, Bernd Hertenstein, Francesco Fabbiano, Richard F. Schlenk, Mariadomenica Divona, Francesco Albano, Mohammed Wattad, Maria Teresa Voso, Christian Thiede, Christian Brandts, Paola Fazi, Gerhard Ehninger, Mathias Hänel, Sergio Amadori, Alessandro Rambaldi, Giorgio La Nasa, Helmut R. Salih, Hartmut Döhner, Michael Lübbert, Giuseppe Avvisati, Arnold Ganser, Erika Borlenghi, Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, and Lo-Coco, F

Subjects
Adult, Male, Oncology, Acute promyelocytic leukemia, Cancer Research, medicine.medical_specialty, Adolescent, Retinoic acid, Tretinoin, Follow-Up Studie, law.invention, Young Adult, chemistry.chemical_compound, Leukemia, Promyelocytic, Acute, Randomized controlled trial, law, Germany, Internal medicine, medicine, acute leukemia, Arsenic trioxide, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, All trans, Hematology, Long term results, Middle Aged, APL, arsenic trioxide, medicine.disease, Clinical trial, Prospective Studie, Leukemia, Treatment Outcome, Italy, chemistry, Female, business, Settore MED/15 - Malattie del Sangue, Human
Published
2019

41. Netboost: Boosting-Supported Network Analysis Improves High-Dimensional Omics Prediction in Acute Myeloid Leukemia and Huntington's Disease.

Author

Schlosser P, Knaus J, Schmutz M, Dohner K, Plass C, Bullinger L, Claus R, Binder H, Lubbert M, and Schumacher M

Subjects
Algorithms, Animals, Cluster Analysis, DNA Methylation genetics, Female, Humans, Machine Learning, Male, Mice, Proportional Hazards Models, Computational Biology methods, Huntington Disease diagnosis, Huntington Disease genetics, Huntington Disease mortality, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality
Abstract

State-of-the art selection methods fail to identify weak but cumulative effects of features found in many high-dimensional omics datasets. Nevertheless, these features play an important role in certain diseases. We present Netboost, a three-step dimension reduction technique. First, a boosting-based filter is combined with the topological overlap measure to identify the essential edges of the network. Second, sparse hierarchical clustering is applied on the selected edges to identify modules and finally module information is aggregated by the first principal components. We demonstrate the application of the newly developed Netboost in combination with CoxBoost for survival prediction of DNA methylation and gene expression data from 180 acute myeloid leukemia (AML) patients and show, based on cross-validated prediction error curve estimates, its prediction superiority over variable selection on the full dataset as well as over an alternative clustering approach. The identified signature related to chromatin modifying enzymes was replicated in an independent dataset, the phase II AMLSG 12-09 study. In a second application we combine Netboost with Random Forest classification and improve the disease classification error in RNA-sequencing data of Huntington's disease mice. Netboost is a freely available Bioconductor R package for dimension reduction and hypothesis generation in high-dimensional omics applications.

Published
2021
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42. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial.

Author

Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts CH, Hanel M, Rollig C, Schmitz N, Link H, Frairia C, Fozza C, Maria D'Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Voso MT, Ehninger G, Schlenk RF, and Lo-Coco F

Subjects
Adolescent, Adult, Aged, Female, Follow-Up Studies, Germany, Humans, Italy, Male, Middle Aged, Prospective Studies, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenic Trioxide administration & dosage, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin administration & dosage
Published
2020
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43. Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML.

Author

Li Z, Huang H, Li Y, Jiang X, Chen P, Arnovitz S, Radmacher MD, Maharry K, Elkahloun A, Yang X, He C, He M, Zhang Z, Dohner K, Neilly MB, Price C, Lussier YA, Zhang Y, Larson RA, Le Beau MM, Caligiuri MA, Bullinger L, Valk PJ, Delwel R, Lowenberg B, Liu PP, Marcucci G, Bloomfield CD, Rowley JD, and Chen J

Subjects
Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Down-Regulation, Female, Gene Expression Profiling, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Leukemia, Myeloid pathology, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Prognosis, Up-Regulation, Young Adult, Homeodomain Proteins genetics, Leukemia, Myeloid genetics, MicroRNAs genetics, Proto-Oncogene Proteins genetics
Abstract

Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.

Published
2012
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44. [Effects of sodium valproate on proliferation and apoptosis of human myelodysplastic syndromes cell line MUTZ-1].

Author

Chen BA, Zhao HH, Gao C, Shao ZY, Xia GH, and Dohner K

Subjects
Cell Cycle drug effects, Cell Line, Cyclin-Dependent Kinase Inhibitor p21 genetics, Dose-Response Relationship, Drug, Humans, Myelodysplastic Syndromes metabolism, RNA, Messenger metabolism, Time, Apoptosis drug effects, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Myelodysplastic Syndromes pathology, Valproic Acid pharmacology
Abstract

Background & Objective: Myelodysplastic syndromes (MDS) are heterogeneous disorders with the expansion of malignant clones. No satisfactory treatment for MDS is available. Sodium valproate (VPA) can inhibit the proliferation of tumor cells by inducing G(0)/G(1) phase arrest and cell apoptosis. This study was to investigate the effects of VPA on the proliferation of MDS cell line MUTZ-1, and explore possible mechanisms., Methods: MUTZ-1 cells were treated with VPA. Cell proliferation was determined by MTT assay. Cell morphology was observed under microscope and transmission electron microscope. Cell apoptosis and cell cycle were analyzed by flow cytometry (FCM). The expression of p21(WAF1) (cyclin-dependent kinase inhibitor) was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot., Results: VPA inhibited the proliferation of MUTZ-1 cells in concentration-and time-dependent manners. When treated with 4 mmol/L VPA for 72 h, typical apoptotic morphologic features appeared in MUTZ-1 cells: condensation of cells and nuclear chromatin, disintegration of nuclear chromatin, and apoptotic bodies were observed under microscope; aggregation and margination of apoptotic nuclear chromatin, cytoplasm condensation, and irregular chromatin masses were observed under transmission electron microscope. The apoptosis rate was significantly higher in the cells treated with 1, 2, and 4 mmol/L VPA for 72 h than in untreated cells [(3.14+/-0.87)%, (14.90+/-1.04)% and (22.46+/-1.74)% vs. (0.99+/-0.35)%, P<0.05]. After treatment of VPA, cell cycle was arrested obviously at G0/G1 phase (P<0.05)û the mRNA and protein levels of p21(WAF1) were up-regulated in MUTZ-1 cells (P<0.05)., Conclusions: VPA could induce G(0)/G(1) phase arrest, inhibit the proliferation and induce the apoptosis of MUTZ-1 cells in vitro. The mechanism may be associated with the up-regulation of p21(WAF1).

Published
2007

45. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML.

Author

Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S, Schlenk RF, Dohner K, Hinrichsen T, Rudolph C, Schambach A, Baum C, Schlegelberger B, Dohner H, Ganser A, and Humphries RK

Subjects
Aged, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Biomarkers, Tumor genetics, Bone Marrow Cells metabolism, Cell Cycle drug effects, Cell Cycle genetics, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Transformation, Viral drug effects, Cell Transformation, Viral genetics, Chromosomal Instability genetics, Disease-Free Survival, Hematopoiesis drug effects, Hematopoiesis genetics, Herpes Simplex Virus Protein Vmw65 biosynthesis, Herpes Simplex Virus Protein Vmw65 genetics, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutagenesis, Insertional drug effects, Mutagenesis, Insertional genetics, Predictive Value of Tests, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins genetics, Repressor Proteins genetics, Retroviridae, Risk Factors, Survival Rate, Trans-Activators, Transduction, Genetic, Tretinoin administration & dosage, Tretinoin pharmacology, Tumor Suppressor Proteins genetics, Biomarkers, Tumor biosynthesis, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Leukemic drug effects, Gene Expression Regulation, Leukemic genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Repressor Proteins biosynthesis, Tumor Suppressor Proteins biosynthesis
Abstract

Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice. Insertional mutagenesis and chromosomal instability were ruled out as secondary aberrations. MN1 increased resistance to all-trans retinoic acid (ATRA)-induced cell-cycle arrest and differentiation by more than 3000-fold in vitro. The differentiation block could be released by fusion of a transcriptional activator (VP16) to MN1 without affecting the ability to immortalize BM cells, suggesting that MN1 blocks differentiation by transcriptional repression. We then evaluated whether MN1 expression levels in patients with AML (excluding M3-AML) correlated with resistance to ATRA treatment in elderly patients uniformly treated within treatment protocol AMLHD98-B. Strikingly, patients with low MN1 expression who received ATRA had a significantly prolonged event-free (P = .008) and overall (P = .04) survival compared with patients with either low MN1 expression and no ATRA, or high MN1 expression with or without ATRA. MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment.

Published
2007
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46. [Apoptosis of human myelodysplastic syndrome cell Line MUTZ-1 induced by sodium valproate].

Author

Zhao HH, Chen BA, Gao C, Shao ZY, Xia GH, Ding JH, Sun YY, Wang J, Cheng J, Zhao G, Dohner K, and Dohner H

Subjects
Cell Cycle drug effects, Cell Line, Dose-Response Relationship, Drug, Humans, Apoptosis drug effects, Myelodysplastic Syndromes pathology, Valproic Acid pharmacology
Abstract

To study the effects of sodium valproate (VPA) on human myelodysplastic syndrome cell line MUTZ-1. The cell proliferation was determined by MTT assay, apoptotic morphological features were observed by light microscopy and transmission electronmicroscopy, cell apoptosis and cell cycle shift were analyzed by flow cytometry (FCM). The results showed that VPA could inhibit the growth of MUTZ-1 cells in dose-and time-dependent manners. The typical apoptotic morphological features appeared in MUTZ-1 cells treated with 4 mmol/L VPA for 72 hours. Pyknosis of cells and nuclei, disintegration of nuclear chromatin and apoptotic body could be observed by light microscopy. Aggregation and margination of nuclear chromatin, concentration of plasm, increment of density and chromatin mass of irregular size could be observed by transmission electronmicroscope. The flow cytometric analysis indicated that the VPA could induce cell apoptosis, apoptosis rate increased in dose-dependent manner, ratio of cells at G(0)/G(1) phase increased and ratio of cells at S phase decreased in dose-dependent manner, the cells were arrested at G(0)/G(1) phase. It is concluded that the VPA can induce apotosis and inhibite proliferation of MUTZ-1 cells via arresting cells at G(0)/G(1) phase.

Published
2007

47. Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches.

Author

Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A, Dohner K, Schlenk RF, Pollack JR, Dohner H, and Bullinger L

Subjects
Animals, Antigens, Neoplasm immunology, COS Cells, Chlorocebus aethiops, Disease-Free Survival, Epitopes immunology, HL-60 Cells, Humans, Immunotherapy methods, K562 Cells, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Peptides immunology, Prognosis, RNA, Neoplasm genetics, RNA, Neoplasm immunology, Survival Rate, Antigens, Neoplasm genetics, Epitopes genetics, Gene Expression Regulation, Leukemic genetics, Gene Expression Regulation, Leukemic immunology, Leukemia, Myeloid, Acute genetics, Peptides genetics
Abstract

The expression of tumor-associated antigens (TAAs) might play a critical role in the control of minimal residual disease (MRD) in acute myeloid leukemia (AML), and therefore might be associated with clinical outcome in AML. In a DNA microarray analysis of 116 AML samples, we found a significant correlation between high mRNA levels of G250/CA9 and longer overall survival (P = .022), a similar trend with high mRNA levels of PRAME (P = .103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1, we found no correlation with clinical outcome. High expression of at least 1 of the 3 TAAs, RHAMM/HMMR, PRAME, or G250/CA9, provided the strongest favorable prognostic effect (P = .005). Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease (P < .001). Furthermore, we could demonstrate specific lysis of T2 cells presenting these epitope peptides. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control. Thus, these TAAs represent interesting targets for polyvalent immunotherapeutic approaches in AML.

Published
2006
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