72 results on '"Ksienzyk B"'
Search Results
2. P1402: ALTERATIONS OF HUMAN BONE MARROW NICHE IN CLONAL HEMATOPOIESIS AND AML
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Dragieva, Y., primary, Rothenberg-Thurley, M., additional, Ksienzyk, B., additional, Hadzic, A., additional, Paulus, A., additional, Tast, B., additional, Subklewe, M., additional, Spiekermann, K., additional, Theurich, S., additional, Metzeler, K., additional, Solovey, M., additional, and Ziemann, F., additional
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- 2022
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3. P17 - Topic: AS04-MDS Biology and Pathogenesis/AS04b-Clonal diversity & evolution: MUTATIONAL PROFILING OF CLONAL HEMATOPOIESIS, MDS AND SAML DEPICTS DIVERSITIES OF CLONAL PROGRESSION
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Hartmann, L., Hecker, J., Rothenberg-Thurley, M., Rivière, J., Ksienzyk, B., Buck, M., Van Der Garde, M., Fischer, L., Winter, S., Rauner, M., Tsourdi, E., Sockel, K., Schneider, M., Kubasch, A.S., Nolde, M., Hausmann, D., Lützner, J., Roth, A., Bassermann, F., Spiekermann, K., Hofbauer, L., Platzbecker, U., Götze, K., and Metzeler, K.
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- 2021
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4. Topic: AS04-MDS Biology and Pathogenesis/AS04b-Clonal diversity & evolution
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Hartmann, L., primary, Hecker, J., additional, Rothenberg-Thurley, M., additional, Rivière, J., additional, Ksienzyk, B., additional, Buck, M., additional, Van Der Garde, M., additional, Fischer, L., additional, Winter, S., additional, Rauner, M., additional, Tsourdi, E., additional, Sockel, K., additional, Schneider, M., additional, Kubasch, A.S., additional, Nolde, M., additional, Hausmann, D., additional, Lützner, J., additional, Roth, A., additional, Bassermann, F., additional, Spiekermann, K., additional, Hofbauer, L., additional, Platzbecker, U., additional, Götze, K., additional, and Metzeler, K., additional
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- 2021
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5. Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia
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Konstandin, N, Bultmann, S, Szwagierczak, A, Dufour, A, Ksienzyk, B, Schneider, F, Herold, T, Mulaw, M, Kakadia, P M, Schneider, S, Spiekermann, K, Leonhardt, H, and Bohlander, S K
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- 2011
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6. Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing
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Greif, P A, Yaghmaie, M, Konstandin, N P, Ksienzyk, B, Alimoghaddam, K, Ghavamzadeh, A, Hauser, A, Graf, A, Krebs, S, Blum, H, and Bohlander, S K
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- 2011
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7. Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing
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Greif, P A, Eck, S H, Konstandin, N P, Benet-Pagès, A, Ksienzyk, B, Dufour, A, Vetter, A T, Popp, H D, Lorenz-Depiereux, B, Meitinger, T, Bohlander, S K, and Strom, T M
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- 2011
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8. Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia: V399
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Konstandin, N. P., Bultmann, S., Szwagierczak, A., Dufour, A., Ksienzyk, B., Schneider, F., Herold, T., Mulaw, M., Kakadia, P. M., Schneider, S., Spiekermann, K., Leonhardt, H., and Bohlander, S. K.
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- 2011
9. Monoallelic CEBPA mutations in normal karyotype AML: Additional gene mutations predict outcome: V29
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Dufour, A., Schneider, F., Hoster, E., Ksienzyk, B., Benthaus, T., Schneider, S., Sauerland, M.-C., Büchner, T., Berdel, W., Wörmann, B., Braess, J., Subklewe, M., Hiddemann, W., Bohlander, S. K., and Spiekermann, K.
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- 2010
10. PF210 CLINICAL ASPECTS AND DIFFERENTIAL SPLICING IN ACUTE MYELOID LEUKEMIA PATIENTS WITH SRSF2, U2AF1 AND SF3B1 MUTATIONS
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Bamopoulos, S., primary, Batcha, A., additional, Jurinovic, V., additional, Rothenberg-Thurley, M., additional, Janke, H., additional, Ksienzyk, B., additional, Philippou-Massier, J., additional, Krebs, S., additional, Blum, H., additional, Schneider, S., additional, Konstandin, N., additional, Sauerland, M., additional, Görlich, D., additional, Berdel, W., additional, Woermann, B., additional, Bohlander, S., additional, Mansmann, U., additional, Hiddemann, W., additional, Braess, J., additional, Spiekermann, K., additional, Metzeler, K., additional, and Herold, T., additional
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- 2019
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11. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia
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Rothenberg-Thurley, M, primary, Amler, S, additional, Goerlich, D, additional, Köhnke, T, additional, Konstandin, N P, additional, Schneider, S, additional, Sauerland, M C, additional, Herold, T, additional, Hubmann, M, additional, Ksienzyk, B, additional, Zellmeier, E, additional, Bohlander, S K, additional, Subklewe, M, additional, Faldum, A, additional, Hiddemann, W, additional, Braess, J, additional, Spiekermann, K, additional, and Metzeler, K H, additional
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- 2017
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12. The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models
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Dutta, S, primary, Krause, A, additional, Vosberg, S, additional, Herold, T, additional, Ksienzyk, B, additional, Quintanilla-Martinez, L, additional, Tizazu, B, additional, Chopra, M, additional, Graf, A, additional, Krebs, S, additional, Blum, H, additional, Greif, P A, additional, Vetter, A, additional, Metzeler, K, additional, Rothenberg-Thurley, M, additional, Schneider, M R, additional, Dahlhoff, M, additional, Spiekermann, K, additional, Zimber-Strobl, U, additional, Wolf, E, additional, and Bohlander, S K, additional
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- 2015
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13. RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes
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Greif, P. A., primary, Konstandin, N. P., additional, Metzeler, K. H., additional, Herold, T., additional, Pasalic, Z., additional, Ksienzyk, B., additional, Dufour, A., additional, Schneider, F., additional, Schneider, S., additional, Kakadia, P. M., additional, Braess, J., additional, Sauerland, M. C., additional, Berdel, W. E., additional, Buchner, T., additional, Woermann, B. J., additional, Hiddemann, W., additional, Spiekermann, K., additional, and Bohlander, S. K., additional
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- 2012
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14. Persistence of Driver Mutations during Complete Remission Associates with Shorter Survival and Contributes to the Inferior Outcomes of Elderly Patients with Acute Myeloid Leukemia
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Rothenberg-Thurley, M., Susanne Amler, Goerlich, D., Sauerland, M. C., Schneider, S., Konstandin, N. P., Batcha, A. M., Ksienzyk, B., Zellmeier, E., Mansmann, U., Subklewe, M., Bohlander, S. K., Faldum, A., Hiddemann, W., Spiekermann, K., Braess, J., and Metzeler, Klaus H.
15. Detection Of Chromosome 9q Deletion in Acute Myeloid Leukemia (AML) Patients Using Targeted Sequencing Data
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Vosberg, S., Herold, T., Klaus Metzeler, Schneider, S., Ksienzyk, B., Graf, A., Krebs, S., Blum, H., Spiekermann, K., Bohlander, S. K., Hiddemann, W., Mansmann, U., and Greif, P. A.
16. The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models
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Dutta S, Krause A, Vosberg S, Herold T, Ksienzyk B, Quintanilla-Martinez L, Tizazu B, Chopra M, Graf A, Krebs S, Blum H, Pa, Greif, Vetter A, Metzeler K, Rothenberg-Thurley M, Schneider MR, Dahlhoff M, Spiekermann K, Zimber-Strobl U, and Eckhard Wolf
17. Persistence of driver mutations during complete remission associates with shorter survival and contributes to the inferior outcomes of elderly patients with acute myeloid leukemia
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Rothenberg-Thurley, M., Susanne Amler, Goerlich, D., Sauerland, M. C., Schneider, S., Konstandin, N. P., Schaaf, S., Batcha, Nazeer A. M., Braeundl, K., Ksienzyk, B., Zellmaier, F., Mansmann, U., Fiegl, M., Subklewe, M., Bohlander, S. K., Faldum, A., Hiddemann, W., Spiekermann, K., Braess, J., Metzeler, K. H., and AMLCG
18. Characterization of Spliceosome Mutations in Patients with Acute Myeloid Leukemia
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Bamopoulos, S. A., Batcha, A. M. N., Jurinovic, V., Metzeler, K. H., Thurley, M. Rothenberg, Ksienzyk, B., Hartmann, L., Greif, P. A., Phillippou-Massier, J., Krebs, S., Blum, H., Susanne Amler, Schneider, S., Konstandin, N., Sauerland, M. C., Berdel, W. E., Woermann, B. J., Bohlander, S. K., Braess, J., Hiddemann, W., Mansmann, U., Spiekermann, K., and Herold, T.
19. Genetic Characterization of AML Patients by Targeted, Deep Sequencing Reveals Patterns of Cooperating Gene Mutations and Detects Subclonal Driver Mutations: Data from the AMLCG-2008 Cohort
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Metzeler, K. H., Rothenberg-Thurley, M., Schneider, S., Tobias Herold, Konstandin, N. P., Dufour, A., Braeundl, K., Ksienzyk, B., Zellmeier, E., Greif, P. A., Fiegl, M., Subklewe, M., Bohlander, S. K., Braess, J., Hiddemann, W., and Spiekermann, K.
20. GENETIC CHARACTERIZATION OF A LARGE GROUP OF CEBPA MUTATED AML PATIENTS AND THE EFFECT OF TET2 AND GATA2 MUTATIONS ON OUTCOME
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Konstandin, N. P., Pastore, F., Dufour, A., Klaus Metzeler, Rothenberg-Thurley, M., Herold, T., Schneider, S., Ksienzyk, B., Tschuri, S., Berdel, W. E., Woermann, B. J., Sauerland, C., Braess, J., Stefan, B. K., Hiddemann, W., and Spiekermann, K.
21. PERSISTENCE OF DRIVER MUTATIONS DURING COMPLETE REMISSION ASSOCIATES WITH SHORTER SURVIVAL AND CONTRIBUTES TO THE INFERIOR OUTCOMES OF ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA
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Rothenberg-Thurley, M., Amler, S., Goerlich, D., Sauerland, M. C., Schneider, S., Konstandin, N. P., Schaaf, S., Batcha, Nazeer A. M., Braeundl, K., Ksienzyk, B., Zellmaier, E., Mansmann, U., Fiegl, M., Subklewe, M., Bohlander, S. K., Faldum, A., Hiddemann, W., Spiekermann, K., Braess, J., and Klaus Metzeler
22. Prediction of Primary Refractory Acute Myeloid Leukemia
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Herold, Tobias, Jurinovic, V., Klaus Metzeler, Batcha, A. M. N., Bamopoulos, S. A., Rothenberg-Thurley, M., Ksienzyk, B., Hartmann, L., Greif, P. A., Phillippou-Massier, J., Krebs, S., Blum, H., Amler, S., Schneider, S., Konstandin, N., Sauerland, M. C., Berdel, W. E., Woermann, B. J., Subklewe, M., Fiegl, M., Bohlander, S. K., Braess, J., Hiddemann, W., Mansmann, U., and Spiekermann, K.
23. The Mutatome of CBFB/MYH11 Rearranged Acute Myeloid Leukemia (AML)
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Opatz, S., Klaus Metzeler, Herold, T., Vosberg, S., Braeundl, K., Ksienzyk, B., Graf, A., Krebs, S., Blum, H., Schneider, S., Konstandin, N., Hiddemann, W., Spiekermann, K., Bohlander, S. K., and Greif, P. A.
24. Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
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Pastore F, Gittinger H, Raab S, Tschuri S, Ksienzyk B, Konstandin NP, Schneider S, Rothenberg-Thurley M, Horny HP, Werner M, Sauerland MC, Amler S, Görlich D, Berdel WE, Wörmann B, Braess J, Hiddemann W, Tischer J, Herold T, Metzeler KH, and Spiekermann K
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- Adult, Humans, Middle Aged, Retrospective Studies, Disease-Free Survival, Neoplasm Recurrence, Local genetics, Chromosome Aberrations, Prognosis, Chromosomes, Leukemia, Megakaryoblastic, Acute genetics, Leukemia, Megakaryoblastic, Acute therapy, Leukemia, Myeloid, Acute genetics, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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25. Germline SNPs previously implicated as prognostic biomarkers do not associate with outcomes in intensively treated AML.
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Batcha AMN, Buckup N, Bamopoulos SA, Jurinovic V, Rothenberg-Thurley M, Gittinger H, Ksienzyk B, Dufour A, Schneider S, Kontro M, Saad J, Heckmann CA, Sauerland C, Görlich D, Berdel WE, Wörmann BJ, Krug U, Braess J, Mansmann U, Hiddemann W, Spiekermann K, Metzeler KH, and Herold T
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- Humans, Prognosis, Biomarkers, Tumor, Polymorphism, Single Nucleotide, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics
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- 2023
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26. Molecular profiling of patients with cytogenetically normal acute myeloid leukemia and hyperleukocytosis.
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Pastore F, Pastore A, Rothenberg-Thurley M, Metzeler KH, Ksienzyk B, Schneider S, Bohlander SK, Braess J, Sauerland MC, Görlich D, Berdel WE, Wörmann B, von Bergwelt-Baildon MS, Hiddemann W, and Spiekermann K
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- Humans, Nucleophosmin, Mutation, Prognosis, fms-Like Tyrosine Kinase 3 genetics, Nuclear Proteins genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Background: Acute myeloid leukemia (AML) with initial hyperleukocytosis is associated with high early mortality and a poor prognosis. The aims of this study were to delineate the underlying molecular landscape in the largest cytogenetic risk group, cytogenetically normal acute myeloid leukemia (CN-AML), and to assess the prognostic relevance of recurrent mutations in the context of hyperleukocytosis and clinical risk factors., Methods: The authors performed a targeted sequencing of 49 recurrently mutated genes in 56 patients with newly diagnosed CN-AML and initial hyperleukocytosis of ≥100 G/L treated in the AMLCG99 study. The median number of mutated genes per patient was 5. The most common mutations occurred in FLT3 (73%), NPM1 (75%), and TET2 (45%)., Results: The predominant pathways affected by mutations were signaling (84% of patients), epigenetic modifiers (75% of patients), and nuclear transport (NPM1; 75%) of patients. AML with hyperleukocytosis was enriched for molecular subtypes that negatively affected the prognosis, including a high percentage of patients presenting with co-occurring mutations in signaling and epigenetic modifiers such as FLT3 internal tandem duplications and TET2 mutations., Conclusions: Despite these unique molecular features, clinical risk factors, including high white blood count, hemoglobin level, and lactate dehydrogenase level at baseline, remained the predictors for overall survival and relapse-free survival in hyperleukocytotic CN-AML., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2022
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27. Compartment-specific mutational landscape of clonal hematopoiesis.
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Hartmann L, Hecker JS, Rothenberg-Thurley M, Rivière J, Jentzsch M, Ksienzyk B, Buck MC, van der Garde M, Fischer L, Winter S, Rauner M, Tsourdi E, Weidner H, Sockel K, Schneider M, Kubasch AS, Nolde M, Hausmann D, Lützner J, Goralski S, Bassermann F, Spiekermann K, Hofbauer LC, Schwind S, Platzbecker U, Götze KS, and Metzeler KH
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- Humans, Hematopoiesis genetics, Mutation, Clone Cells, Clonal Hematopoiesis genetics, Myeloproliferative Disorders
- Abstract
Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH., (© 2022. The Author(s).)
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- 2022
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28. A clinically applicable gene expression-based score predicts resistance to induction treatment in acute myeloid leukemia.
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Moser C, Jurinovic V, Sagebiel-Kohler S, Ksienzyk B, Batcha AMN, Dufour A, Schneider S, Rothenberg-Thurley M, Sauerland CM, Görlich D, Berdel WE, Krug U, Mansmann U, Hiddemann W, Braess J, Spiekermann K, Greif PA, Vosberg S, Metzeler KH, Kumbrink J, and Herold T
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- Cohort Studies, Cytogenetics, Gene Expression, Humans, Prognosis, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Prediction of resistant disease at initial diagnosis of acute myeloid leukemia (AML) can be achieved with high accuracy using cytogenetic data and 29 gene expression markers (Predictive Score 29 Medical Research Council; PS29MRC). Our aim was to establish PS29MRC as a clinically usable assay by using the widely implemented NanoString platform and further validate the classifier in a more recently treated patient cohort. Analyses were performed on 351 patients with newly diagnosed AML intensively treated within the German AML Cooperative Group registry. As a continuous variable, PS29MRC performed best in predicting induction failure in comparison with previously published risk models. The classifier was strongly associated with overall survival. We were able to establish a previously defined cutoff that allows classifier dichotomization (PS29MRCdic). PS29MRCdic significantly identified induction failure with 59% sensitivity, 77% specificity, and 72% overall accuracy (odds ratio, 4.81; P = 4.15 × 10-10). PS29MRCdic was able to improve the European Leukemia Network 2017 (ELN-2017) risk classification within every category. The median overall survival with high PS29MRCdic was 1.8 years compared with 4.3 years for low-risk patients. In multivariate analysis including ELN-2017 and clinical and genetic markers, only age and PS29MRCdic were independent predictors of refractory disease. In patients aged ≥60 years, only PS29MRCdic remained as a significant variable. In summary, we confirmed PS29MRC as a valuable classifier to identify high-risk patients with AML. Risk classification can still be refined beyond ELN-2017, and predictive classifiers might facilitate clinical trials focusing on these high-risk patients with AML., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2021
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29. CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease.
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Hecker JS, Hartmann L, Rivière J, Buck MC, van der Garde M, Rothenberg-Thurley M, Fischer L, Winter S, Ksienzyk B, Ziemann F, Solovey M, Rauner M, Tsourdi E, Sockel K, Schneider M, Kubasch AS, Nolde M, Hausmann D, Paulus AC, Lützner J, Roth A, Bassermann F, Spiekermann K, Marr C, Hofbauer LC, Platzbecker U, Metzeler KH, and Götze KS
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- Adult, Aged, Aged, 80 and over, Autoimmune Diseases complications, Cells, Cultured, DNA Methyltransferase 3A genetics, DNA-Binding Proteins genetics, Dioxygenases genetics, Humans, Male, Middle Aged, Young Adult, Arthroplasty, Replacement, Hip, Autoimmune Diseases genetics, Clonal Hematopoiesis, Gene Frequency, Mutation
- Abstract
Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone-derived cells as healthy experimental controls., (© 2021 by The American Society of Hematology.)
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- 2021
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30. Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.
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Herold T, Rothenberg-Thurley M, Grunwald VV, Janke H, Goerlich D, Sauerland MC, Konstandin NP, Dufour A, Schneider S, Neusser M, Ksienzyk B, Greif PA, Subklewe M, Faldum A, Bohlander SK, Braess J, Wörmann B, Krug U, Berdel WE, Hiddemann W, Spiekermann K, and Metzeler KH
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- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Induction Chemotherapy methods, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation genetics, Prognosis, Risk Assessment methods, Risk Factors, Survival Rate, Treatment Outcome, Young Adult, Leukemia, Myeloid, Acute genetics
- Abstract
The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18-86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.
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- 2020
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31. Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.
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Bamopoulos SA, Batcha AMN, Jurinovic V, Rothenberg-Thurley M, Janke H, Ksienzyk B, Philippou-Massier J, Graf A, Krebs S, Blum H, Schneider S, Konstandin N, Sauerland MC, Görlich D, Berdel WE, Woermann BJ, Bohlander SK, Canzar S, Mansmann U, Hiddemann W, Braess J, Spiekermann K, Metzeler KH, and Herold T
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- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Leukemia, Myeloid, Acute genetics, Mutation, Phosphoproteins genetics, RNA Splicing, RNA Splicing Factors genetics, Serine-Arginine Splicing Factors genetics, Splicing Factor U2AF genetics
- Abstract
Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.
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- 2020
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32. The clinical mutatome of core binding factor leukemia.
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Opatz S, Bamopoulos SA, Metzeler KH, Herold T, Ksienzyk B, Bräundl K, Tschuri S, Vosberg S, Konstandin NP, Wang C, Hartmann L, Graf A, Krebs S, Blum H, Schneider S, Thiede C, Middeke JM, Stölzel F, Röllig C, Schetelig J, Ehninger G, Krämer A, Braess J, Görlich D, Sauerland MC, Berdel WE, Wörmann BJ, Hiddemann W, Spiekermann K, Bohlander SK, and Greif PA
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- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Young Adult, Core Binding Factors genetics, Leukemia, Myeloid, Acute genetics
- Abstract
The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.
- Published
- 2020
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33. Loss of KDM6A confers drug resistance in acute myeloid leukemia.
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Stief SM, Hanneforth AL, Weser S, Mattes R, Carlet M, Liu WH, Bartoschek MD, Domínguez Moreno H, Oettle M, Kempf J, Vick B, Ksienzyk B, Tizazu B, Rothenberg-Thurley M, Quentmeier H, Hiddemann W, Vosberg S, Greif PA, Metzeler KH, Schotta G, Bultmann S, Jeremias I, Leonhardt H, and Spiekermann K
- Subjects
- Animals, Heterografts, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Mice, Mutation, Drug Resistance, Neoplasm physiology, Histone Demethylases genetics, Histone Demethylases metabolism, Leukemia, Myeloid, Acute pathology
- Abstract
Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.
- Published
- 2020
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34. Allelic Imbalance of Recurrently Mutated Genes in Acute Myeloid Leukaemia.
- Author
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Batcha AMN, Bamopoulos SA, Kerbs P, Kumar A, Jurinovic V, Rothenberg-Thurley M, Ksienzyk B, Philippou-Massier J, Krebs S, Blum H, Schneider S, Konstandin N, Bohlander SK, Heckman C, Kontro M, Hiddemann W, Spiekermann K, Braess J, Metzeler KH, Greif PA, Mansmann U, and Herold T
- Subjects
- Female, Gene Expression Regulation, Leukemic genetics, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute pathology, Male, Mutation, Neoplasm Recurrence, Local pathology, Nucleophosmin, Prognosis, Allelic Imbalance genetics, Leukemia, Myeloid, Acute genetics, Neoplasm Proteins genetics, Neoplasm Recurrence, Local genetics
- Abstract
The patho-mechanism of somatic driver mutations in cancer usually involves transcription, but the proportion of mutations and wild-type alleles transcribed from DNA to RNA is largely unknown. We systematically compared the variant allele frequencies of recurrently mutated genes in DNA and RNA sequencing data of 246 acute myeloid leukaemia (AML) patients. We observed that 95% of all detected variants were transcribed while the rest were not detectable in RNA sequencing with a minimum read-depth cut-off (10x). Our analysis focusing on 11 genes harbouring recurring mutations demonstrated allelic imbalance (AI) in most patients. GATA2, RUNX1, TET2, SRSF2, IDH2, PTPN11, WT1, NPM1 and CEBPA showed significant AIs. While the effect size was small in general, GATA2 exhibited the largest allelic imbalance. By pooling heterogeneous data from three independent AML cohorts with paired DNA and RNA sequencing (N = 253), we could validate the preferential transcription of GATA2-mutated alleles. Differential expression analysis of the genes with significant AI showed no significant differential gene and isoform expression for the mutated genes, between mutated and wild-type patients. In conclusion, our analyses identified AI in nine out of eleven recurrently mutated genes. AI might be a common phenomenon in AML which potentially contributes to leukaemogenesis.
- Published
- 2019
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35. Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older.
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Prassek VV, Rothenberg-Thurley M, Sauerland MC, Herold T, Janke H, Ksienzyk B, Konstandin NP, Goerlich D, Krug U, Faldum A, Berdel WE, Wörmann B, Braess J, Schneider S, Subklewe M, Bohlander SK, Hiddemann W, Spiekermann K, and Metzeler KH
- Subjects
- Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Male, Mutation, Nucleophosmin, Risk Assessment, Survival Rate, Biomarkers, Tumor genetics, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Nuclear Proteins genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
A cute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65-70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classification systems and identify additional factors associated with outcomes in intensively treated patients aged ≥75 years. In 151 patients who received induction chemotherapy in the AMLCG-1999 trial, we investigated recurrently mutated genes using a targeted sequencing assay covering 64 genes. The median number of mutated genes per patient was four. The most commonly mutated genes were TET2 (42%), DNMT3A (35%), NPM1 (32%), SRSF2 (25%) and ASXL1 (21%). The complete remission rate was 44% and the 3-year survival was 21% for the entire cohort. While adverse-risk cytogenetics (MRC classification) were associated with shorter overall survival ( P =0.001), NPM1 and FLT3 -ITD mutations (present in 18%) did not have a significant impact on overall survival. Notably, none of the 13 IDH1 -mutated patients (9%) reached complete remission. Consequently, the overall survival of this subgroup was significantly shorter than that of IDH1 -wildtype patients ( P <0.001). In summary, even among very old, intensively treated, acute myeloid leukemia patients, adverse-risk cytogenetics predict inferior survival. The spectrum and relevance of driver gene mutations in elderly patients differs from that in younger patients. Our data implicate IDH1 mutations as a novel marker for chemorefractory disease and inferior prognosis. (AMLCG-1999 trial: clinicaltrials.gov identifier, NCT00266136)., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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36. Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA .
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Konstandin NP, Pastore F, Herold T, Dufour A, Rothenberg-Thurley M, Hinrichsen T, Ksienzyk B, Tschuri S, Schneider S, Hoster E, Berdel WE, Woermann BJ, Sauerland MC, Braess J, Bohlander SK, Klein HG, Hiddemann W, Metzeler KH, and Spiekermann K
- Subjects
- Adolescent, Adult, Aged, CCAAT-Enhancer-Binding Proteins metabolism, Female, Humans, Male, Middle Aged, Mutation, Prognosis, Young Adult, CCAAT-Enhancer-Binding Protein-alpha genetics, CCAAT-Enhancer-Binding Proteins genetics, Cytogenetics methods, Genetic Heterogeneity drug effects
- Abstract
Biallelic mutations of the CCAAT/enhancer binding protein α ( CEBPA ) gene define a distinct genetic entity of acute myeloid leukemia (AML) with favorable prognosis. The presence of GATA2 and CSF3R mutations that are specifically associated with this subgroup but not mutated in all samples suggests a genetic heterogeneity of bi CEBPA -mutated AML. We characterized the mutational landscape of CEBPA -mutated cytogenetically normal AML by targeted amplicon resequencing. We analyzed 48 biallelically mutated CEBPA (bi CEBPA ), 32 monoallelically mutated CEBPA (mo CEBPA ), and 287 wild-type CEBPA (wt CEBPA ) patient samples from German AML Cooperative Group studies or registry. Targeted sequencing of 42 genes revealed that mo CEBPA patients had significantly more additional mutations and additional mutated genes than bi CEBPA patients. Within the group of bi CEBPA patients, we identified 2 genetic subgroups defined by the presence or absence of mutations in chromatin/DNA modifiers (C), cohesin complex (C), and splicing (S) genes: bi CEBPA
CCSpos (25/48 [52%]) and bi CEBPACCSneg (23/48 [48%]). Equivalent subgroups were identified in 51 bi CEBPA patients from the Cancer Genome Project. Patients in the bi CEBPACCSpos group were significantly older and had poorer overall survival and lower complete remission rates following intensive chemotherapy regimens compared with patients in the bi CEBPACCSneg group. Patients with available remission samples from the bi CEBPACCSpos group cleared the bi CEBPA mutations, but most had persisting CCS mutations in complete remission, suggesting the presence of a preleukemic clone. In conclusion, CCS mutations define a distinct biological subgroup of bi CEBPA AML that might refine prognostic classification of AML. This trial was registered at www.clinicaltrials.gov as #NCT00266136 and NCT01382147., (© 2018 by The American Society of Hematology.)- Published
- 2018
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37. Clonal heterogeneity of FLT3 -ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia.
- Author
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Schranz K, Hubmann M, Harin E, Vosberg S, Herold T, Metzeler KH, Rothenberg-Thurley M, Janke H, Bräundl K, Ksienzyk B, Batcha AMN, Schaaf S, Schneider S, Bohlander SK, Görlich D, Berdel WE, Wörmann BJ, Braess J, Krebs S, Hiddemann W, Mansmann U, Spiekermann K, and Greif PA
- Abstract
In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3- ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3- ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3- ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%). The total number of ITDs detected by HTAS was higher than in routine diagnostics ( n = 312 vs. n = 274). In particular, HTAS detected a higher number of ITDs per patient compared to fragment analysis, indicating higher sensitivity for subclonal ITDs. Patients with more than one ITD according to HTAS had a significantly shorter overall and relapse free survival. There was a close correlation between FLT3- ITD mRNA levels in fragment analysis and variant allele frequency in HTAS. However, the abundance of long ITDs (≥75nt) was underestimated by HTAS, as the size of the ITD affected the mappability of the corresponding sequence reads. In summary, this study demonstrates that HTAS is a feasible approach for FLT3- ITD detection in AML patients, delivering length, position, sequence and mutational burden of this alteration in a single assay with high sensitivity. Our findings provide insights into the clonal architecture of FLT3- ITD positive AML and have clinical implications., Competing Interests: CONFLICTS OF INTEREST The authors have no conflict of interest to declare.
- Published
- 2018
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38. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia.
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Rothenberg-Thurley M, Amler S, Goerlich D, Köhnke T, Konstandin NP, Schneider S, Sauerland MC, Herold T, Hubmann M, Ksienzyk B, Zellmeier E, Bohlander SK, Subklewe M, Faldum A, Hiddemann W, Braess J, Spiekermann K, and Metzeler KH
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Bone Marrow pathology, Combined Modality Therapy, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Mutation, Neoplasm, Residual pathology, Proportional Hazards Models, Recurrence, Remission Induction, Risk Assessment, Treatment Outcome, Young Adult, Biomarkers, Tumor, Clonal Evolution genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology
- Abstract
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio (HR), 2.34; p = 0.0039) and overall survival (HR, 2.14; p = 0.036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide post-remission treatment.
- Published
- 2018
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39. Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients.
- Author
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Greif PA, Hartmann L, Vosberg S, Stief SM, Mattes R, Hellmann I, Metzeler KH, Herold T, Bamopoulos SA, Kerbs P, Jurinovic V, Schumacher D, Pastore F, Bräundl K, Zellmeier E, Ksienzyk B, Konstandin NP, Schneider S, Graf A, Krebs S, Blum H, Neumann M, Baldus CD, Bohlander SK, Wolf S, Görlich D, Berdel WE, Wörmann BJ, Hiddemann W, and Spiekermann K
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Line, Cytarabine pharmacology, Cytogenetics methods, DNA (Cytosine-5-)-Methyltransferases genetics, Drug Resistance drug effects, Drug Resistance genetics, Epigenesis, Genetic drug effects, Epigenesis, Genetic genetics, Female, Histone Demethylases genetics, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Mutation drug effects, Mutation genetics, Recurrence, Remission Induction methods, Exome Sequencing methods, Young Adult, Exome genetics, Leukemia, Myeloid, Acute genetics
- Abstract
Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse. Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. Clin Cancer Res; 24(7); 1716-26. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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40. A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia.
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Herold T, Jurinovic V, Batcha AMN, Bamopoulos SA, Rothenberg-Thurley M, Ksienzyk B, Hartmann L, Greif PA, Phillippou-Massier J, Krebs S, Blum H, Amler S, Schneider S, Konstandin N, Sauerland MC, Görlich D, Berdel WE, Wörmann BJ, Tischer J, Subklewe M, Bohlander SK, Braess J, Hiddemann W, Metzeler KH, Mansmann U, and Spiekermann K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Gene Expression Profiling, Humans, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Mutation, Predictive Value of Tests, Prognosis, Randomized Controlled Trials as Topic, Survival Analysis, Young Adult, Drug Resistance, Neoplasm genetics, Leukemia, Myeloid, Acute diagnosis, Machine Learning, Remission Induction methods
- Abstract
Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expression markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addition, a cut off was defined to divide patients into a high-risk and a low-risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P =8.63·10
-9 , AUC=0.76) and as a dichotomous classifier (OR=8.03, P =4.29·10-9 ); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P =0.0011; dichotomous: OR=4.44, P =0.00021) were left as significant variables. PS29MRC dominated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined ( P =4.01·10-10 ). PS29MRC will make it possible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification., (Copyright© 2018 Ferrata Storti Foundation.)- Published
- 2018
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41. Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1, DNMT3A, WT1 and low expression of TLE4.
- Author
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Herold T, Metzeler KH, Vosberg S, Hartmann L, Jurinovic V, Opatz S, Konstandin NP, Schneider S, Zellmeier E, Ksienzyk B, Graf A, Krebs S, Blum H, Cristina Sauerland M, Büchner T, Berdel WE, Wörmann BJ, Mansmann U, Hiddemann W, Bohlander SK, Spiekermann K, and Greif PA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Chromosome Aberrations, Cohort Studies, DNA Methyltransferase 3A, Exome genetics, Female, Follow-Up Studies, High-Throughput Nucleotide Sequencing methods, Humans, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neoplasm Staging, Nucleophosmin, Prognosis, Survival Rate, Young Adult, Chromosome Deletion, Chromosomes, Human, Pair 9 genetics, DNA (Cytosine-5-)-Methyltransferases genetics, Leukemia, Myeloid, Acute genetics, Mutation genetics, Nuclear Proteins genetics, Repressor Proteins genetics, WT1 Proteins genetics
- Abstract
Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations. We detected frequent mutations in NPM1 (10/26; 38%), DNMT3A (8/26; 31%), and WT1 (8/26; 31%) but only few FLT3-ITDs (2/26; 8%). All mutations affecting NPM1 and DNMT3A were exclusively identified in patients with del(9q) as the sole abnormality and were significantly more frequent compared to 111 patients classified as intermediate-II according to the European LeukemiaNet (10/14, 71% vs. 22/111, 20%; P < 0.001, 8/14, 57% vs. 26/111, 23%; P = 0.02). Furthermore, we identified DNMT3B to be rarely but recurrently targeted by truncating mutations in AML. Gene expression analysis of 13 patients with del(9q) and 454 patients with normal karyotype or various cytogenetic aberrations showed significant down regulation of TLE4 in patients with del(9q) (P = 0.02). Interestingly, downregulation of TLE4 was not limited to AML with del(9q), potentially representing a common mechanism in AML pathogenesis. Our comprehensive genetic analysis of the del(9q) subgroup reveals a unique mutational profile with the frequency of DNMT3A mutations in the del(9q) only subset being the highest reported so far in AML, indicating oncogenic cooperativity. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
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42. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.
- Author
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Herold T, Schneider S, Metzeler KH, Neumann M, Hartmann L, Roberts KG, Konstandin NP, Greif PA, Bräundl K, Ksienzyk B, Huk N, Schneider I, Zellmeier E, Jurinovic V, Mansmann U, Hiddemann W, Mullighan CG, Bohlander SK, Spiekermann K, Hoelzer D, Brüggemann M, Baldus CD, Dreyling M, and Gökbuget N
- Subjects
- Adolescent, Adult, Cluster Analysis, DNA Copy Number Variations, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Humans, Male, Middle Aged, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Survival Analysis, Translocation, Genetic, Young Adult, Immunoglobulin Heavy Chains genetics, Janus Kinase 2 genetics, Mutation, Neoplasm, Residual pathology, Oncogene Proteins, Fusion genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, Cytokine genetics
- Abstract
Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the "remaining BCP-ALL" cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Ph-like ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed. (NCT00199056, NCT00198991)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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43. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.
- Author
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Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, Schneider S, Konstandin NP, Dufour A, Bräundl K, Ksienzyk B, Zellmeier E, Hartmann L, Greif PA, Fiegl M, Subklewe M, Bohlander SK, Krug U, Faldum A, Berdel WE, Wörmann B, Büchner T, Hiddemann W, Braess J, and Spiekermann K
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cytogenetic Analysis, DNA Mutational Analysis, Female, Gene Frequency genetics, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Multivariate Analysis, Nucleophosmin, Prognosis, Risk Factors, Survival Analysis, Young Adult, Leukemia, Myeloid, Acute genetics, Mutation genetics
- Abstract
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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44. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.
- Author
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Hartmann L, Dutta S, Opatz S, Vosberg S, Reiter K, Leubolt G, Metzeler KH, Herold T, Bamopoulos SA, Bräundl K, Zellmeier E, Ksienzyk B, Konstandin NP, Schneider S, Hopfner KP, Graf A, Krebs S, Blum H, Middeke JM, Stölzel F, Thiede C, Wolf S, Bohlander SK, Preiss C, Chen-Wichmann L, Wichmann C, Sauerland MC, Büchner T, Berdel WE, Wörmann BJ, Braess J, Hiddemann W, Spiekermann K, and Greif PA
- Subjects
- Base Sequence, Cell Line, Tumor, Chromosomes, Human, Pair 21 chemistry, Chromosomes, Human, Pair 21 metabolism, Chromosomes, Human, Pair 8 chemistry, Chromosomes, Human, Pair 8 metabolism, Core Binding Factor Alpha 2 Subunit metabolism, DNA-Binding Proteins metabolism, Gene Expression Profiling, Glycolysis genetics, HEK293 Cells, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Oncogene Proteins, Fusion metabolism, Protein Domains, RUNX1 Translocation Partner 1 Protein metabolism, Signal Transduction, Survival Analysis, Transcription Factors metabolism, Core Binding Factor Alpha 2 Subunit genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Mutation, Oncogene Proteins, Fusion genetics, RUNX1 Translocation Partner 1 Protein genetics, Transcription Factors genetics, Translocation, Genetic
- Abstract
The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.
- Published
- 2016
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45. The NPM1 mutation type has no impact on survival in cytogenetically normal AML.
- Author
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Pastore F, Greif PA, Schneider S, Ksienzyk B, Mellert G, Zellmeier E, Braess J, Sauerland CM, Heinecke A, Krug U, Berdel WE, Buechner T, Woermann B, Hiddemann W, and Spiekermann K
- Subjects
- Adult, Aged, Cytarabine therapeutic use, Daunorubicin therapeutic use, Female, Gene Expression, Humans, Induction Chemotherapy methods, Karyotyping, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mitoxantrone therapeutic use, Nucleophosmin, Prognosis, Remission Induction, Risk Factors, Survival Analysis, Thioguanine therapeutic use, Treatment Outcome, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Mutation, Nuclear Proteins genetics
- Abstract
NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML.
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- 2014
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46. Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.
- Author
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Herold T, Metzeler KH, Vosberg S, Hartmann L, Röllig C, Stölzel F, Schneider S, Hubmann M, Zellmeier E, Ksienzyk B, Jurinovic V, Pasalic Z, Kakadia PM, Dufour A, Graf A, Krebs S, Blum H, Sauerland MC, Büchner T, Berdel WE, Woermann BJ, Bornhäuser M, Ehninger G, Mansmann U, Hiddemann W, Bohlander SK, Spiekermann K, and Greif PA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 13 genetics, Chromosomes, Human, Pair 13 metabolism, Disease-Free Survival, Female, Germany epidemiology, Humans, Male, Middle Aged, Survival Rate, Gene Expression Regulation, Leukemic genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Trisomy genetics, Trisomy pathology, Up-Regulation genetics
- Abstract
In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373., (© 2014 by The American Society of Hematology.)
- Published
- 2014
- Full Text
- View/download PDF
47. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia.
- Author
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Pastore F, Dufour A, Benthaus T, Metzeler KH, Maharry KS, Schneider S, Ksienzyk B, Mellert G, Zellmeier E, Kakadia PM, Unterhalt M, Feuring-Buske M, Buske C, Braess J, Sauerland MC, Heinecke A, Krug U, Berdel WE, Buechner T, Woermann B, Hiddemann W, Bohlander SK, Marcucci G, Spiekermann K, Bloomfield CD, and Hoster E
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, CCAAT-Enhancer-Binding Proteins genetics, DNA Mutational Analysis, Disease-Free Survival, Female, Genetic Predisposition to Disease, Germany, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Nuclear Proteins genetics, Nucleophosmin, Phenotype, Predictive Value of Tests, Proportional Hazards Models, Recurrence, Reproducibility of Results, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Cytogenetic Analysis, Decision Support Techniques, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics., Patients and Methods: Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study (www.aml-score.org)., Results: On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials., Conclusion: We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML., (© 2014 by American Society of Clinical Oncology.)
- Published
- 2014
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48. Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
- Author
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Opatz S, Polzer H, Herold T, Konstandin NP, Ksienzyk B, Zellmeier E, Vosberg S, Graf A, Krebs S, Blum H, Hopfner KP, Kakadia PM, Schneider S, Dufour A, Braess J, Sauerland MC, Berdel WE, Büchner T, Woermann BJ, Hiddemann W, Spiekermann K, Bohlander SK, and Greif PA
- Subjects
- Adolescent, Adult, Amino Acid Substitution, Apoptosis drug effects, Base Sequence, Benzothiazoles pharmacology, Cell Proliferation drug effects, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic pathology, Cytokines pharmacology, DNA Mutational Analysis, Female, Gene Expression Regulation, Leukemic drug effects, Gene Rearrangement, Humans, Leukemia genetics, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Oncogene Proteins, Fusion genetics, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors pharmacology, Staurosporine analogs & derivatives, Staurosporine pharmacology, fms-Like Tyrosine Kinase 3 chemistry, Core Binding Factor beta Subunit genetics, Exome genetics, Mutation genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.
- Published
- 2013
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49. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations.
- Author
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Neumann M, Heesch S, Schlee C, Schwartz S, Gökbuget N, Hoelzer D, Konstandin NP, Ksienzyk B, Vosberg S, Graf A, Krebs S, Blum H, Raff T, Brüggemann M, Hofmann WK, Hecht J, Bohlander SK, Greif PA, and Baldus CD
- Subjects
- Adolescent, Adult, Aged, DNA Methyltransferase 3A, Epigenesis, Genetic, Female, Follow-Up Studies, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Prognosis, Receptor, Notch1 genetics, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Biomarkers, Tumor genetics, DNA (Cytosine-5-)-Methyltransferases genetics, Exome genetics, Mutation genetics, Precursor Cells, T-Lymphoid pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a high-risk subgroup of T-lineage ALL characterized by specific stem cell and myeloid features. In adult ETP-ALL, no comprehensive studies on the genetic background have been performed to elucidate molecular lesions of this distinct subgroup. We performed whole-exome sequencing of 5 paired ETP-ALL samples. In addition to mutations in genes known to be involved in leukemogenesis (ETV6, NOTCH1, JAK1, and NF1), we identified novel recurrent mutations in FAT1 (25%), FAT3 (20%), DNM2 (35%), and genes associated with epigenetic regulation (MLL2, BMI1, and DNMT3A). Importantly, we verified the high rate of DNMT3A mutations (16%) in a larger cohort of adult patients with ETP-ALL (10/68). Mutations in epigenetic regulators support clinical trials, including epigenetic-orientated therapies, for this high-risk subgroup. Interestingly, more than 60% of adult patients with ETP-ALL harbor at least a single genetic lesion in DNMT3A, FLT3, or NOTCH1 that may allow use of targeted therapies.
- Published
- 2013
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50. GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.
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Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B, Sturm J, Benthaus T, Herold T, Yaghmaie M, Dörge P, Hopfner KP, Hauser A, Graf A, Krebs S, Blum H, Kakadia PM, Schneider S, Hoster E, Schneider F, Stanulla M, Braess J, Sauerland MC, Berdel WE, Büchner T, Woermann BJ, Hiddemann W, Spiekermann K, and Bohlander SK
- Subjects
- Adult, Alleles, Amino Acid Sequence, Base Sequence, CCAAT-Enhancer-Binding Proteins metabolism, Cytogenetic Analysis, DNA Mutational Analysis, DNA, Neoplasm genetics, Exome, GATA2 Transcription Factor chemistry, Gene Frequency, Humans, Karyotype, Leukemia, Myeloid, Acute metabolism, Models, Molecular, Molecular Sequence Data, Prognosis, Transcriptional Activation, Zinc Fingers genetics, CCAAT-Enhancer-Binding Proteins genetics, GATA2 Transcription Factor genetics, Leukemia, Myeloid, Acute genetics, Mutation
- Abstract
Cytogenetically normal acute myeloid leukemia (CN-AML) with biallelic CEBPA gene mutations (biCEPBA) represents a distinct disease entity with a favorable clinical outcome. So far, it is not known whether other genetic alterations cooperate with biCEBPA mutations during leukemogenesis. To identify additional mutations, we performed whole exome sequencing of 5 biCEBPA patients and detected somatic GATA2 zinc finger 1 (ZF1) mutations in 2 of 5 cases. Both GATA2 and CEBPA are transcription factors crucial for hematopoietic development. Inherited or acquired mutations in both genes have been associated with leukemogenesis. Further mutational screening detected novel GATA2 ZF1 mutations in 13 of 33 biCEBPA-positive CN-AML patients (13/33, 39.4%). No GATA2 mutations were found in 38 CN-AML patients with a monoallelic CEBPA mutation and in 89 CN-AML patients with wild-type CEBPA status. The presence of additional GATA2 mutations (n=10) did not significantly influence the clinical outcome of 26 biCEBPA-positive patients. In reporter gene assays, all tested GATA2 ZF1 mutants showed reduced capacity to enhance CEBPA-mediated activation of transcription, suggesting that the GATA2 ZF1 mutations may collaborate with biCEPBA mutations to deregulate target genes during malignant transformation. We thus provide evidence for a genetically distinct subgroup of CN-AML. The German AML cooperative group trials 1999 and 2008 are registered with the identifiers NCT00266136 and NCT01382147 at www.clinicaltrials.gov.
- Published
- 2012
- Full Text
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