22 results on '"Behre, Gerhard"'
Search Results
2. Clinical impact of clonal hematopoiesis in acute myeloid leukemia patients receiving allogeneic transplantation.
- Author
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Grimm J, Bill M, Jentzsch M, Beinicke S, Häntschel J, Goldmann K, Schulz J, Cross M, Franke GN, Behre G, Vucinic V, Pönisch W, Lange T, Niederwieser D, and Schwind S
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Hematopoiesis genetics, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Transplantation Conditioning methods, Transplantation, Homologous methods
- Abstract
Age-related somatic mutations linked to clonal hematopoiesis have been found in apparently healthy individuals and increase the risk of developing hematologic malignancies. In acute myeloid leukemia (AML) the clinical relevance of clonal hematopoiesis remains controversial and data on patients with detectable clonal hematopoiesis, consolidated with hematopoietic stem cell transplantation are limited. We analyzed samples from 113 AML patients in complete remission prior to hematopoietic stem cell transplantation for the presence of clonal hematopoiesis-associated mutations. The results were correlated with clinical and biological data. In complete remission we found 75 mutations previously linked to clonal hematopoiesis in 47 patients (41.6%). Twenty patients had ≥2 mutations linked to clonal hematopoiesis. DNMT3A, TET2, and ASXL1 were most frequently mutated. When compared to pre-treatment samples we found variable patterns of mutation persistence depending on the gene mutated. In AML patients after allogeneic hematopoietic stem cell transplantation the presence of clonal hematopoiesis-associated mutations in complete remission did not associate with inferior clinical outcome. This study demonstrates that clonal hematopoiesis is a frequent phenomenon in AML patients. Presence of clonal hematopoiesis has no negative prognostic impact in the context of an allogeneic hematopoietic stem cell transplantation and might be beneficial if certain genes are affected.
- Published
- 2019
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3. Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia.
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Hilger N, Mueller C, Stahl L, Mueller AM, Zoennchen B, Dluczek S, Halbich C, Wickenhauser C, Gerloff D, Wurm AA, Behre G, Kretschmer A, and Fricke S
- Subjects
- Animals, Apoptosis, CD4 Antigens immunology, Disease Models, Animal, Flow Cytometry, Graft vs Host Disease etiology, Graft vs Leukemia Effect immunology, Humans, Immunoglobulin G pharmacology, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mice, Mice, Knockout, Prognosis, Transplantation, Homologous, fms-Like Tyrosine Kinase 3 metabolism, CD4 Antigens antagonists & inhibitors, Hematopoietic Stem Cell Transplantation adverse effects, Immunoglobulin G immunology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3
ITD AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG1 prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3ITD AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.- Published
- 2018
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4. Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients.
- Author
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Bill M, Grimm J, Jentzsch M, Kloss L, Goldmann K, Schulz J, Beinicke S, Häntschel J, Cross M, Vucinic V, Pönisch W, Behre G, Franke GN, Lange T, Niederwieser D, and Schwind S
- Subjects
- Adult, Aged, Allografts, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor analysis, Biomarkers, Tumor blood, Bone Marrow chemistry, Bone Marrow Transplantation, CCAAT-Enhancer-Binding Proteins analysis, Combined Modality Therapy, DNA, Neoplasm genetics, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Neoplasm Proteins analysis, Neoplasm Proteins blood, Neoplasm, Residual, Nuclear Proteins analysis, Nuclear Proteins blood, Nucleophosmin, Peripheral Blood Stem Cell Transplantation, Prognosis, Recurrence, Remission Induction, Retrospective Studies, Sensitivity and Specificity, Transplantation Conditioning methods, Treatment Outcome, fms-Like Tyrosine Kinase 3 analysis, Leukemia, Myeloid, Acute pathology, Mutation, Neoplasm Proteins genetics, Nuclear Proteins genetics, Polymerase Chain Reaction methods, Preoperative Care
- Abstract
Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable ("minimal") residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers-also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients' outcomes.
- Published
- 2018
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5. MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia.
- Author
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Hartmann JU, Bräuer-Hartmann D, Kardosova M, Wurm AA, Wilke F, Schödel C, Gerloff D, Katzerke C, Krakowsky R, Namasu CY, Bill M, Schwind S, Müller-Tidow C, Niederwieser D, Alberich-Jorda M, and Behre G
- Subjects
- 3' Untranslated Regions, Animals, Antagomirs metabolism, Apoptosis, Cell Differentiation, Cell Proliferation, Granulocytes cytology, Granulocytes metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Mice, Mice, Inbred C57BL, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Mitogen-Activated Protein Kinase 7 chemistry, Mitogen-Activated Protein Kinase 7 genetics, Prognosis, Survival Rate, Leukemia, Myeloid, Acute pathology, MicroRNAs metabolism, Mitogen-Activated Protein Kinase 7 metabolism
- Abstract
Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34
+ HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.- Published
- 2018
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6. Prognostic relevance of DNMT3A R882 mutations in AML patients undergoing non-myeloablative conditioning hematopoietic stem cell transplantation.
- Author
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Schmalbrock LK, Bonifacio L, Bill M, Jentzsch M, Schubert K, Grimm J, Cross M, Lange T, Vucinic V, Pönisch W, Behre G, Franke GN, Niederwieser D, and Schwind S
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- Adult, Aged, DNA Methyltransferase 3A, Humans, Leukemia, Myeloid, Acute therapy, Middle Aged, Prognosis, Retrospective Studies, Transplantation Conditioning methods, Treatment Outcome, DNA (Cytosine-5-)-Methyltransferases genetics, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute genetics, Mutation
- Published
- 2018
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7. miR-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia.
- Author
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Krakowsky RHE, Wurm AA, Gerloff D, Katzerke C, Bräuer-Hartmann D, Hartmann JU, Wilke F, Thiede C, Müller-Tidow C, Niederwieser D, and Behre G
- Subjects
- Female, Gene Expression Regulation, Leukemic, Humans, Leukemia, Myeloid, Acute drug therapy, Male, RNA Interference, Drug Resistance, Neoplasm genetics, Leukemia, Myeloid, Acute genetics, MicroRNAs genetics, Repetitive Sequences, Nucleic Acid, Sequence Deletion, fms-Like Tyrosine Kinase 3 genetics
- Published
- 2018
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8. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).
- Author
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Mellinghoff SC, Panse J, Alakel N, Behre G, Buchheidt D, Christopeit M, Hasenkamp J, Kiehl M, Koldehoff M, Krause SW, Lehners N, von Lilienfeld-Toal M, Löhnert AY, Maschmeyer G, Teschner D, Ullmann AJ, Penack O, Ruhnke M, Mayer K, Ostermann H, Wolf HH, and Cornely OA
- Subjects
- Clinical Trials as Topic, Drug Monitoring, Hematology, Hematopoietic Stem Cell Transplantation, Humans, Induction Chemotherapy, Invasive Fungal Infections immunology, Invasive Fungal Infections microbiology, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute pathology, Medical Oncology, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes pathology, Societies, Medical, Triazoles therapeutic use, Voriconazole therapeutic use, Antifungal Agents therapeutic use, Immunocompromised Host, Invasive Fungal Infections prevention & control, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Primary Prevention methods
- Abstract
Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.
- Published
- 2018
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9. Disruption of the C/EBPα-miR-182 balance impairs granulocytic differentiation.
- Author
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Wurm AA, Zjablovskaja P, Kardosova M, Gerloff D, Bräuer-Hartmann D, Katzerke C, Hartmann JU, Benoukraf T, Fricke S, Hilger N, Müller AM, Bill M, Schwind S, Tenen DG, Niederwieser D, Alberich-Jorda M, and Behre G
- Subjects
- Animals, Blotting, Western, CCAAT-Enhancer-Binding Proteins metabolism, Cell Differentiation genetics, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Mice, Mice, Knockout, MicroRNAs metabolism, Prognosis, Real-Time Polymerase Chain Reaction, CCAAT-Enhancer-Binding Proteins genetics, Granulocytes, Leukemia, Myeloid, Acute genetics, Leukopoiesis genetics, MicroRNAs genetics
- Abstract
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
- Published
- 2017
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10. Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation.
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Jentzsch M, Bill M, Nicolet D, Leiblein S, Schubert K, Pless M, Bergmann U, Wildenberger K, Schuhmann L, Cross M, Pönisch W, Franke GN, Vucinic V, Lange T, Behre G, Mrózek K, Bloomfield CD, Niederwieser D, and Schwind S
- Subjects
- Adult, Aged, Allografts, Disease-Free Survival, Female, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prognosis, Recurrence, Survival Rate, Young Adult, ADP-ribosyl Cyclase 1 analysis, Antigens, CD34 analysis, Leukemia, Myeloid, Acute pathology, Neoplastic Stem Cells pathology
- Abstract
In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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11. EVI2B is a C/EBPα target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.
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Zjablovskaja P, Kardosova M, Danek P, Angelisova P, Benoukraf T, Wurm AA, Kalina T, Sian S, Balastik M, Delwel R, Brdicka T, Tenen DG, Behre G, Fiore F, Malissen B, Horejsi V, and Alberich-Jorda M
- Subjects
- Animals, Apoptosis, Bone Marrow Cells cytology, CCAAT-Enhancer-Binding Protein-alpha genetics, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Down-Regulation drug effects, Estradiol pharmacology, Granulocyte Colony-Stimulating Factor pharmacology, Granulocytes cytology, Granulocytes metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myeloid, Acute metabolism, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins genetics, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering metabolism, CCAAT-Enhancer-Binding Protein-alpha metabolism, Leukemia, Myeloid, Acute pathology, Membrane Glycoproteins metabolism, Membrane Proteins metabolism
- Abstract
Development of hematopoietic populations through the process of differentiation is critical for proper hematopoiesis. The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is a master regulator of myeloid differentiation, and the identification of C/EBPα target genes is key to understand this process. Here we identified the Ecotropic Viral Integration Site 2B (EVI2B) gene as a direct target of C/EBPα. We showed that the product of the gene, the transmembrane glycoprotein EVI2B (CD361), is abundantly expressed on the surface of primary hematopoietic cells, the highest levels of expression being reached in mature granulocytes. Using shRNA-mediated downregulation of EVI2B in human and murine cell lines and in primary hematopoietic stem and progenitor cells, we demonstrated impaired myeloid lineage development and altered progenitor functions in EVI2B-silenced cells. We showed that the compromised progenitor functionality in Evi2b-depleted cells can be in part explained by deregulation of cell proliferation and apoptosis. In addition, we generated an Evi2b knockout murine model and demonstrated altered properties of hematopoietic progenitors, as well as impaired G-CSF dependent myeloid colony formation in the knockout cells. Remarkably, we found that EVI2B is significantly downregulated in human acute myeloid leukemia samples characterized by defects in CEBPA. Altogether, our data demonstrate that EVI2B is a downstream target of C/EBPα, which regulates myeloid differentiation and functionality of hematopoietic progenitors.
- Published
- 2017
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12. The Janus-faced Nature of miR-22 in Hematopoiesis: Is It an Oncogenic Tumor Suppressor or Rather a Tumor-Suppressive Oncogene?
- Author
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Wurm AA, Tenen DG, and Behre G
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- Genes, Tumor Suppressor, Hematopoiesis, Humans, Macrophages, MicroRNAs, Leukemia, Myeloid, Acute, Monocytes
- Abstract
Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
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13. Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation.
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Pfrepper C, Klink A, Behre G, Schenk T, Franke GN, Jentzsch M, Schwind S, Al-Ali HK, Hochhaus A, Niederwieser D, and Sayer HG
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- Adult, Aged, Amsacrine administration & dosage, Combined Modality Therapy, Cytarabine administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prognosis, Remission Induction, Retrospective Studies, Risk Factors, Survival Rate, Transplantation Conditioning, Transplantation, Homologous, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation mortality, Leukemia, Myeloid, Acute therapy, Neoplasm Recurrence, Local therapy
- Abstract
Introduction: Hematopoietic stem cell transplantation (HCT) is considered a standard treatment for high-risk acute myeloid leukemia (AML) in first or second complete remission (CR). Unfortunately, not all patients achieve complete remission prior to HCT. We sought to establish predictive factors for survival after HCT for refractory AML after FLAMSA-RIC., Patients and Methods: We analyzed the outcome of 44 consecutive patients aged between 21 and 65 years transplanted at the University Hospitals of Jena and Leipzig for refractory AML between 2006 and January 2013. Conditioning for HCT was performed with chemotherapy consisting of fludarabine, cytarabine, and amsacrine followed by total body irradiation or busulfan combined with cyclophosphamide. Antithymocyte globulin was given when transplanting from unrelated donors (FLAMSA-RIC)., Results: Estimated overall survival (OS) and event-free survival (EFS) at 3 years after a median follow-up of 34 (range 6-71) months were 15 and 12 %, respectively. Causes of death were relapse in 66 %, infection in 11 %, and graft-versus-host disease (GvHD) in 7 % of all patients. Twenty-five from 42 evaluable patients (60 %) achieved CR 4 weeks after HCT, while eight patients had partial remission (PR), and nine patients had stable disease (SD). Another six patients with PR and SD achieved CR (overall CR rate 74 %) from 4 weeks to day 90 after HCT following reduction in immunosuppression. The strongest favorable factors in univariate analysis for OS, EFS, and RI were ≥98 % total donor chimerism 2-4 weeks after HCT and <3 lines of pretreatment prior to HCT. In addition, better OS was detected in patients with <20 % bone marrow blasts alone (32 vs. 5 % at 3 years) and in combination with <3 lines of pretreatment (38 vs. 4 % at 3 years). Only a trend for better EFS and lower RI was observed in patients with limited chronic GvHD. In addition, a lower RI was seen in patients with <5 % blasts 4 weeks after HCT. Multivariate analysis revealed that ≥98 % donor chimerism 2-4 weeks after HCT for OS, EFS, and RI and <3 lines of pretreatment for OS and EFS are the strongest predictors for better outcome., Conclusion: FLAMSA-RIC shows long-term survival in refractory AML patients. Factors for favorable outcome are <20 % bone marrow blasts prior to HCT, <3 lines of pretreatment and complete donor chimerism after HCT.
- Published
- 2016
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14. CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation.
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Federzoni EA, Humbert M, Torbett BE, Behre G, Fey MF, and Tschan MP
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- Cell Differentiation, Cell Line, Tumor, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Humans, CCAAT-Enhancer-Binding Proteins metabolism, Hexokinase metabolism, Kruppel-Like Transcription Factors metabolism, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Neutrophils metabolism, Neutrophils pathology
- Abstract
The basic leucine zipper transcription factor CCAAT/enhancer binding protein alpha (CEBPA) codes for a critical regulator during neutrophil differentiation. Aberrant expression or function of this protein contributes to the development of acute myeloid leukemia (AML). In this study, we identified two novel unrelated CEBPA target genes, the glycolytic enzyme hexokinase 3 (HK3) and the krüppel-like factor 5 (KLF5) transcription factor, by comparing gene profiles in two cohorts of CEBPA wild-type and mutant AML patients. In addition, we found CEBPA-dependent activation of HK3 and KLF5 transcription during all-trans retinoic acid (ATRA) mediated neutrophil differentiation of acute promyelocytic leukemia (APL) cells. Moreover, we observed direct regulation of HK3 by CEBPA, whereas our data suggest an indirect regulation of KLF5 by this transcription factor. Altogether, our data provide an explanation for low HK3 and KLF5 expression in particular AML subtype and establish these genes as novel CEBPA targets during neutrophil differentiation.
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- 2014
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15. Transcription factor C/EBPα-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia.
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Katzerke C, Madan V, Gerloff D, Bräuer-Hartmann D, Hartmann JU, Wurm AA, Müller-Tidow C, Schnittger S, Tenen DG, Niederwieser D, and Behre G
- Subjects
- Animals, Cell Differentiation physiology, Chromatin Immunoprecipitation, Down-Regulation, Gene Expression Regulation, Neoplastic, Granulocytes metabolism, Humans, Immunoblotting, Leukemia, Myeloid, Acute genetics, Leukopoiesis physiology, Mice, Mice, Knockout, MicroRNAs genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Transfection, CCAAT-Enhancer-Binding Protein-alpha metabolism, Granulocytes cytology, Leukemia, Myeloid, Acute metabolism, MicroRNAs metabolism, Receptor, Notch1 metabolism
- Abstract
The transcription factor CCAAT enhancer binding protein α (C/EBPα) is a master regulator in granulopoiesis and is frequently disrupted in acute myeloid leukemia (AML). We have previously shown that C/EBPα exerts its effects by regulating microRNAs (miRs) such as miR-223 and miR-34a. Here, we confirm miR-30c as a novel important target of C/EBPα during granulopoiesis. Thus, wild-type C/EBPα-p42 directly upregulates miR-30c expression, whereas C/EBPα-p30, found in AML, does not. miR-30c is downregulated in AML, especially in normal karyotype AML patients with CEBPA mutations. An induced C/EBPα knockout in mice leads to a significant downregulation of miR-30c expression in bone marrow cells. We identified NOTCH1 as a direct target of miR-30c. Finally, a block of miR-30c prevents C/EBPα-induced downregulation of Notch1 protein and leads to a reduced CD11b expression in myeloid differentiation. Our study presents the first evidence that C/EBPα, miR-30c, and Notch1 together play a critical role in granulocytic differentiation and AML, and particularly in AML with CEBPA mutations. These data reveal the importance of deregulated miRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML.
- Published
- 2013
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16. The actin-binding protein CORO1A is a novel PU.1 (SPI1)- and CEBPA-regulated gene with significantly lower expression in APL and CEBPA-mutated AML patients.
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Federzoni EA, Humbert M, Valk PJ, Behre G, Leibundgut EO, Torbett BE, Fey MF, and Tschan MP
- Subjects
- CCAAT-Enhancer-Binding Proteins biosynthesis, CCAAT-Enhancer-Binding Proteins metabolism, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Promyelocytic, Acute metabolism, Microfilament Proteins biosynthesis, Microfilament Proteins metabolism, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism, Transcription, Genetic, CCAAT-Enhancer-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Leukemia, Promyelocytic, Acute genetics, Microfilament Proteins genetics, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Published
- 2013
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17. C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations.
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Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, Christopeit M, Nibourel O, Müller-Tidow C, Bohlander SK, Tenen DG, and Behre G
- Subjects
- Blotting, Western, CCAAT-Enhancer-Binding Proteins genetics, Cell Cycle, Cell Differentiation, Chromatin Immunoprecipitation, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, E2F3 Transcription Factor genetics, Flow Cytometry, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Luciferases metabolism, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, CCAAT-Enhancer-Binding Proteins metabolism, E2F3 Transcription Factor metabolism, Granulocytes cytology, Leukemia, Myeloid, Acute genetics, Leukopoiesis, MicroRNAs physiology, Mutation genetics
- Abstract
The transcription factor, CCAAT enhancer binding protein alpha (C/EBPα), is crucial for granulopoiesis and is deregulated by various mechanisms in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported in 10% of human patients with AML. Even though the C/EBPα mutants are known to display distinct biologic function during leukemogenesis, the molecular basis for this subtype of AML remains elusive. We have recently showed the significance of deregulation of C/EBPα-regulated microRNA (miR) in AML. In this study, we report that miR-34a is a novel target of C/EBPα in granulopoiesis. During granulopoiesis, miR-34a targets E2F3 and blocks myeloid cell proliferation. Analysis of AML samples with CEBPA mutations revealed a lower expression of miR-34a and elevated levels of E2F3 as well as E2F1, a transcriptional target of E2F3. Manipulation of miR-34a reprograms granulocytic differentiation of AML blast cells with CEBPA mutations. These results define miR-34a as a novel therapeutic target in AML with CEBPA mutations.
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- 2010
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18. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia.
- Author
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Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK, Tenen DG, and Behre G
- Subjects
- Animals, Base Sequence, CCAAT-Enhancer-Binding Protein-alpha genetics, CCAAT-Enhancer-Binding Protein-alpha metabolism, Cell Cycle, Cell Line, DNA Primers genetics, Down-Regulation, Feedback, Physiological, Granulocytes metabolism, Granulocytes pathology, Humans, K562 Cells, Leukemia, Myeloid, Acute pathology, Leukopoiesis genetics, Leukopoiesis physiology, Mice, Mice, Knockout, Models, Biological, Mutation, Up-Regulation, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is essential for granulopoiesis and its function is deregulated in leukemia. Inhibition of E2F1, the master regulator of cell-cycle progression, by C/EBPalpha is pivotal for granulopoiesis. Recent studies show microRNA-223 (miR-223), a transcriptional target of C/EBPalpha, as a critical player during granulopoiesis. In this report, we demonstrate that during granulopoiesis microRNA-223 targets E2F1. E2F1 protein was up-regulated in miR-223 null mice. We show that miR-223 blocks cell-cycle progression in myeloid cells. miR-223 is down-regulated in different subtypes of acute myeloid leukemia (AML). We further show that E2F1 binds to the miR-223 promoter in AML blast cells and inhibits miR-223 transcription, suggesting that E2F1 is a transcriptional repressor of the miR-223 gene in AML. Our study supports a molecular network involving miR-223, C/EBPalpha, and E2F1 as major components of the granulocyte differentiation program, which is deregulated in AML.
- Published
- 2010
- Full Text
- View/download PDF
19. Target proteins of C/EBPalphap30 in AML: C/EBPalphap30 enhances sumoylation of C/EBPalphap42 via up-regulation of Ubc9.
- Author
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Geletu M, Balkhi MY, Peer Zada AA, Christopeit M, Pulikkan JA, Trivedi AK, Tenen DG, and Behre G
- Subjects
- CCAAT-Enhancer-Binding Proteins genetics, Cell Differentiation genetics, Gene Expression Regulation, Leukemic, Gene Silencing, Genes, Dominant physiology, Granulocytes cytology, Humans, K562 Cells, Lysine metabolism, Models, Biological, Mutant Proteins genetics, Mutant Proteins metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, Receptors, Estrogen genetics, Transcriptional Activation, CCAAT-Enhancer-Binding Proteins metabolism, CCAAT-Enhancer-Binding Proteins physiology, Leukemia, Myeloid, Acute genetics, Mutant Proteins physiology, Protein Processing, Post-Translational genetics, SUMO-1 Protein metabolism, Ubiquitin-Conjugating Enzymes genetics, Up-Regulation
- Abstract
CCAAT/enhancer-binding protein alpha (C/EBPalpha) is a critical regulator for early myeloid differentiation. Mutations in C/EBPalpha occur in 10% of patients with acute myeloid leukemia (AML), leading to the expression of a 30-kDa dominant-negative isoform (C/EBPalphap30). In the present study, using a global proteomics approach to identify the target proteins of C/EBPalphap30, we show that Ubc9, an E2-conjugating enzyme essential for sumoylation, is increased in its expression when C/EBPalphap30 is induced. We confirmed the increased expression of Ubc9 in patients with AML with C/EBPalphap30 mutations compared with other subtypes. We further confirmed that the increase of Ubc9 expression was mediated through increased transcription. Furthermore, we show that Ubc9-mediated enhanced sumoylation of C/EBPalphap42 decreases the transactivation capacity on a minimal C/EBPalpha promoter. Importantly, overexpression of C/EBPalphap30 in granulocyte colony-stimulating factor (G-CSF)-stimulated human CD34(+) cells leads to a differentiation block, which was overcome by the siRNA-mediated silencing of Ubc9. In summary, our data indicate that Ubc9 is an important C/EBPalphap30 target through which C/EBPalphap30 enhances the sumoylation of C/EBPalphap42 to inhibit granulocytic differentiation.
- Published
- 2007
- Full Text
- View/download PDF
20. The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner.
- Author
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Elsässer A, Franzen M, Kohlmann A, Weisser M, Schnittger S, Schoch C, Reddy VA, Burel S, Zhang DE, Ueffing M, Tenen DG, Hiddemann W, and Behre G
- Subjects
- Core Binding Factor Alpha 2 Subunit, Granulocyte Colony-Stimulating Factor physiology, Humans, JNK Mitogen-Activated Protein Kinases, Phosphorylation, Proto-Oncogene Mas, RUNX1 Translocation Partner 1 Protein, Signal Transduction, Transcriptional Activation, U937 Cells, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Genes, jun, Leukemia, Myeloid, Acute genetics, Mitogen-Activated Protein Kinases physiology, Oncogene Proteins, Fusion genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun genetics, Transcription Factor AP-1 physiology, Transcription Factors genetics, Translocation, Genetic
- Abstract
Overexpression of proto-oncogene c-jun and constitutive activation of the Jun N-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression and the role of the JNK signaling pathway have not been investigated in primary acute myeloid leukemia (AML) cells with frequently observed balanced rearrangements such as t(8;21). In the present study, we report elevated c-jun mRNA expression in AML patient bone marrow cells with t(8;21), t(15;17) or inv(16), and a high correlation in mRNA expression levels of AML1-ETO and c-jun within t(8;21)-positive AML patient cells. In myeloid U937 cells, c-jun mRNA and protein expression increase upon inducible expression of AML1-ETO. AML1-ETO transactivates the human c-jun promoter through the proximal activator protein (AP-1) site by activating the JNK pathway. Overexpression of JNK-inhibitor JIP-1 and chemical JNK inhibitors reduce the transactivation capacity of AML1-ETO on the c-jun promoter and the proapoptotic function of AML1-ETO in U937 cells. An autocrine mechanism involving granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor (G-CSF-R) might participate in AML1-ETO mediated JNK-signaling, because AML1-ETO induces G-CSF and G-CSF-R expression, and G-CSF-R-neutralizing antibodies reduce AML1-ETO-induced JNK phosphorylation. These data suggest a model in which AML1-ETO induces proto-oncogene c-jun expression via the proximal AP-1 site of the c-jun promoter in a JNK-dependent manner.
- Published
- 2003
- Full Text
- View/download PDF
21. Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction.
- Author
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Rangatia J, Vangala RK, Singh SM, Peer Zada AA, Elsässer A, Kohlmann A, Haferlach T, Tenen DG, Hiddemann W, and Behre G
- Subjects
- Cell Differentiation, Cell Division, Down-Regulation, Flow Cytometry, Humans, JNK Mitogen-Activated Protein Kinases, Leucine Zippers, Leukemia, Myeloid, Acute metabolism, Mitogen-Activated Protein Kinases chemistry, Models, Molecular, Oligonucleotide Array Sequence Analysis, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Mas, RNA, Messenger metabolism, Tumor Cells, Cultured, CCAAT-Enhancer-Binding Protein-alpha antagonists & inhibitors, DNA metabolism, Leukemia, Myeloid, Acute enzymology, Mitogen-Activated Protein Kinases biosynthesis
- Abstract
Transcription factor C/EBPalpha induces normal myeloid differentiation, inactivation of C/EBPalpha leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPalpha results in AML growth arrest and differentiation. Recent reports suggest that C/EBPalpha is activated or inactivated via protein-protein interactions. We previously reported that C/EBPalpha needs to inactivate the proto-oncogene c-Jun via leucine zipper domain interaction in order to induce granulocytic differentiation. We, therefore, hypothesized that c-Jun expression might be elevated in AML and subsequently inactivate C/EBPalpha. In fact, compared to normal bone marrow mononuclear cells, c-Jun expression is increased in AML patient samples (Affymetrix expression microarray analysis, n=166). c-Jun binds to C/EBPalpha via the leucine zipper domains and prevents C/EBPalpha from DNA binding. Inactivation of C/EBPalpha by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPalpha. The dominant-negative 30-kDa C/EBPalpha protein, found in AML, fails to downregulate c-Jun mRNA expression in AML patient samples. Thus, our data suggest a model for AML in which c-Jun promotes proliferation and prevents differentiation by inhibiting C/EBPalpha DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPalpha and c-Jun, if inhibition of C/EBPalpha by c-Jun or if inhibition of c-Jun by C/EBPalpha is more predominant: proliferation versus differentiation; AML versus normal myeloid development.
- Published
- 2003
- Full Text
- View/download PDF
22. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.
- Author
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Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, Hiddemann W, and Behre G
- Subjects
- Animals, Binding Sites, Bone Marrow Cells cytology, Cell Differentiation, Cell Division, Core Binding Factor Alpha 2 Subunit, Down-Regulation drug effects, Humans, Leukemia, Myeloid, Acute etiology, Mice, Oncogene Proteins, Fusion metabolism, Oncogene Proteins, Fusion pharmacology, Protein Binding, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-jun, RUNX1 Translocation Partner 1 Protein, Trans-Activators metabolism, Transcription Factors metabolism, Transcription Factors pharmacology, Transcription, Genetic drug effects, Tumor Cells, Cultured, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Oncogene Proteins, Fusion physiology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins physiology, Trans-Activators genetics, Trans-Activators physiology, Transcription Factors physiology, Translocation, Genetic
- Abstract
The transcription factor PU.1 plays a pivotal role in normal myeloid differentiation. PU.1(-/-) mice exhibit a complete block in myeloid differentiation. Heterozygous PU.1 mutations were reported in some patients with acute myeloid leukemia (AML), but not in AML with translocation t(8;21), which gives rise to the fusion gene AML1-ETO. Here we report a negative functional impact of AML1-ETO on the transcriptional activity of PU.1. AML1-ETO physically binds to PU.1 in t(8;21)(+) Kasumi-1 cells. AML1-ETO binds to the beta(3)beta(4) region in the DNA-binding domain of PU.1 and displaces the coactivator c-Jun from PU.1, thus down-regulating the transcriptional activity of PU.1. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA-binding capacity of PU.1. AML1-ETO down-regulates the transactivation capacity of PU.1 in myeloid U937 cells, and the expression levels of PU.1 target genes in AML French-American-British (FAB) subtype M2 patients with t(8;21) were lower than in patients without t(8;21). Conditional expression of AML1-ETO causes proliferation in mouse bone marrow cells and inhibits antiproliferative function of PU.1. Overexpression of PU.1, however, differentiates AML1-ETO-expressing Kasumi-1 cells to the monocytic lineage. Thus, the function of PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation.
- Published
- 2003
- Full Text
- View/download PDF
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