246 results on '"Behre, Gerhard"'
Search Results
202. Neurotoxicity upon infusion of dimethylsulfoxide-cryopreserved peripheral blood stem cells in patients with and without pre-existing cerebral disease.
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Mueller, Lutz P., Theurich, Sebastian, Christopeit, Maximilian, Grothe, Wilfried, Muetherig, Anke, Weber, Thomas, Guenther, Susanne, and Behre, Gerhard
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STEM cells , *CARDIOVASCULAR diseases , *NEUROTOXICOLOGY , *SPASMS , *EPILEPSY , *HEMATOPOIETIC stem cell transplantation , *ELECTROLYTES - Abstract
Objective: Toxicity related to the infusion of dimethylsulfoxide (DMSO)-cryopreserved peripheral blood stem cells (DMSO-PBSC) mainly comprises cardiovascular events. Fatal neurotoxicity has been reported in a few cases. DMSO represents the putative causative agent of such rare toxicities and elaborate strategies to replace DMSO would benefit from the identification of predisposing factors for DMSO-related toxicities. Methods: Here, we report on DMSO-related neurotoxicity in a series of patients ( n = 51) receiving DMSO-PBSC. The analyzed patient-series included eight patients with pre-existing cerebral disease, partially with a history of epileptic seizures. Results: Neurotoxicity was observed in only one patient who suffered from a generalized tonic seizure upon infusion of DMSO-PBSC and for which the clinical course is reported herein. No neurotoxicity was observed in the group of patients with pre-existing neurological disease. Furthermore, no neurotoxicity was observed in patients who received particularly large volumes of DMSO. In all patients, mild non-neurological side effects occurred but besides the reported seizure no other severe adverse events were observed upon PBSC-infusion. Conclusions: To our knowledge, this is the first report addressing the identification of predisposing factors for DMSO-related neurotoxicty. We conclude that infusion of DMSO-PBSC can be performed safely in patients with pre-existing cerebral disease despite the rare occurrence of severe neurotoxicity. Retrospective multicenter studies are warranted to identify patients who would benefit from elaborate methods of DMSO-replacement. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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203. 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.
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Elsässer, Annika, Franzen, Michael, Kohlmann, Alexander, Weisser, Martin, Schnittger, Susanne, Schoch, Claudia, Reddy, Venkateshwar A, Burel, Sebastian, Zhang, Dong-Er, Ueffing, Marius, Tenen, Daniel G, Hiddemann, Wolfgang, and Behre, Gerhard
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ONCOGENES , *ACUTE myeloid leukemia , *BONE marrow cells , *MESSENGER RNA , *PROMOTERS (Genetics) - 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.Oncogene (2003) 22, 5646-5657. doi:10.1038/sj.onc.1206673 [ABSTRACT FROM AUTHOR]
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- 2003
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204. Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPa DNA binding via leucine zipper domain interaction.
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Rangatia, Janki, Vangala, Rajani K, Singh, Sheo M, Peer Zada, Abdul A, Elsasser, Annika, Kohlmann, Alexander, Haferlach, Torsten, Tenen, Daniel G, Hiddemann, Wolfgang, and Behre, Gerhard
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TRANSCRIPTION factors , *PROTEINS , *MYELOID leukemia , *DNA , *LEUCINE , *AMINO acids , *CELL physiology , *MEDICAL genetics - Abstract
Transcription factor C/EBPa induces normal myeloid differentiation, inactivation of C/EBPa leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPa results in AML growth arrest and differentiation. Recent reports suggest that C/EBPa is activated or inactivated via protein-protein interactions. We previously reported that C/EBPa 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/EBPa. 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/EBPa via the leucine zipper domains and prevents C/EBPa from DNA binding. Inactivation of C/EBPa by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPa. The dominant-negative 30-kDa C/EBPa 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/EBPa DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPa and c-Jun, if inhibition of C/EBPa by c-Jun or if inhibition of c-Jun by C/EBPa is more predominant: proliferation versus differentiation; AML versus normal myeloid development.Oncogene (2003) 22, 4760-4764. doi:10.1038/sj.onc.1206664 [ABSTRACT FROM AUTHOR]
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- 2003
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205. Downregulation of c-Jun expression and cell cycle regulatory molecules in acute myeloid leukemia cells upon CD44 ligation.
- Author
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Zada, Abdul A Peer, Singh, Sheo M, Reddy, Venkateshwar A, Elsasser, Annika, Meisel, Alexander, Haferlach, Torsten, Tenen, Daniel G, Hiddemann, Wolfgang, and Behre, Gerhard
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JUN oncogenes , *GENE expression , *CELL cycle , *MYELOID leukemia - Abstract
In the present study, we investigated the mechanism of CD44 ligation with the anti-CD44 monoclonal antibody A3D8 to inhibit the proliferation of human acute myeloid leukemia (AML) cells. The effects of A3D8 on myeloid cells were associated with specific disruption of cell cycle events and induction of G0/G1 arrest. Induction of G0/G1 arrest was accompanied by an increase in the expression of p21, attenuation of pRb phosphorylation and associated with decreased Cdk2 and Cdk4 kinase activities. Since c-Jun is an important regulator of proliferation and cell cycle progression, we analysed its role in A3D8-mediated growth arrest. We observed that A3D8 treatment of AML patient blasts and HL60/U937 cells led to the downregulation of c-Jun expression at mRNA and protein level. Transient transfection studies showed the inhibition of c-jun promoter activity by A3D8, involving both AP-1 sites. Furthermore, A3D8 treatment caused a decrease in JNK protein expression and a decrease in the level of phosphorylated c-Jun. Ectopic overexpression of c-Jun in HL60 cells was able to induce proliferation and prevent the antiproliferative effects of A3D8. In summary, these data identify an important functional role of c-Jun in the induction of cell cycle arrest and proliferation arrest of myeloid leukemia cells because of the ligation of the cell surface adhesion receptor CD44 by anti-CD44 antibody. Moreover, targeting of G1 regulatory proteins and the resulting induction of G1 arrest by A3D8 may provide new insights into antiproliferative and differentiation therapy of AML.Oncogene (2003) 22, 2296-2308. doi:10.1038/sj.onc.1206393 [ABSTRACT FROM AUTHOR]
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- 2003
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206. IGFBP3 inhibit die Tumorgenen Eigenschaften der NSCLC-Zelllinie H1299
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Petersen, Marie Anna, Aigner, Achim, Behre, Gerhard, and Universität Leipzig
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Lungenkrebs, IGFBP3, Tumor, NSCLC ,ddc:610 - Abstract
Im Rahmen dieser Arbeit wurden Untersuchungen zur möglichen therapeutischen Bedeutung von IGFBP3 (Insulin-like-Growth Factor Binding Protein 3) beim Lungenkrebs in vitro durchgeführt. Es handelt sich bei IGFBP3 um das Hauptbin- dungsprotein für IGF (Insulin-like-Growth Factor), welches nachweißlich Einfluss auf die Regulation des IGF-Signalwegs und damit auf Zellwachstum, Zellprolifera- tion und Apoptose hat. Für die Untersuchungen wurde die NSCLC-Zelllinie H1299 stabil mit einem Vektor für das Gen IGFBP3 transfiziert. Als Kontrolle dienten einerseits die H1299-Zellen ohne Vektor, wie auch Zellen, welche nur den Vektor ohne cDNA enthielten. Bei den Untersuchungen sollte geklärt werden, inwieweit die Überexpression von IGFBP3 die Proliferation, Migration, Invasion und die Chemosensitivität von NSCLC (non small cell lung cancer) Zellen beeinflusst. Ziel war die Beantwortung der Frage, ob IGFBP3 die tumorgenen Eigenschaften von Lungenkarzinomzellen verändern kann und dadurch ein neues und interessantes Forschungsobjekt für die Therapie von Lungentumoren darstellt.:INHALTSVERZEICHNIS 1 ABKÜRZUNGSVERZEICHNIS 3 1 EINFÜHRUNG 5 1.1 Lungenkrebs 5 1.1.1 Histologische Einteilung 6 1.1.2 Stadieneinteilung und Therapieoptionen 7 1.1.3 Zugelassenes Chemotherapeutikum Cisplatin 8 1.2 Tumorgene Eigenschaften 9 1.2.1 Tumorentstehung und Proliferation 9 1.2.2 Invasion 10 1.2.3 Migration 11 1.2.4 Angiogenese 12 1.3 IGF-Achse 12 1.3.1 IGF und IGF-Rezeptoren 13 1.3.2 IGF-Signalweg 14 1.3.3 IGFBPs 16 1.3.3.1 Struktur von IGFBP3 17 1.3.3.2 Funktionale Rolle von IGFBP3 18 1.4 Zellkulturen 19 1.4.1 NSCLC-Zelllinie H1299 20 1.4.2 pIRES-EGFP-Vektor 20 2 ZIELSTELLUNG 21 3 MATERIALIEN & METHODEN 23 3.1 Verwendete Materialien 23 3.1.1 Zelllinie & Vektor (Tab. 1) 23 3.1.2 Zellmedien (Tab. 2) 23 3.1.3 Chemikalien & Reagenzien (Tab. 3) 23 3.1.4 Gebrauchslösungen & Gele (Tab. 4) 25 3.1.5 Kommerzielle Assays / Kits (Tab. 5) 25 3.1.6 Laborbedarf, Geräte & Software (Tab. 6) 26 3.2 Methoden 29 3.2.1 Kultivieren der Zelllinie 29 3.2.1.1 Auftauen der Zellen 29 3.2.1.2 Umsetzen, Splitten und Passagieren der Zellen 30 3.2.1.3 Bestimmung der Transfektionsrate & Sortieren von Zellen 30 3.2.1.4 Zellen zählen 31 3.2.2 Versuchsaufbau Nachweis IGFBP3 Produktion und Einfluss auf das 2D-Wachstum 32 3.2.3 Versuchsaufbau Nachweis IGF-1-Bindung durch IGFBP3 32 3.2.4 Versuchsaufbau Bestimmung der 3D Proliferation & der Invasion 33 3.2.5 Versuchsaufbau Bestimmung der Migration 34 3.2.6 Zelllysate und Überstände für ELISA-Versuche 343.2.7 ELISA-Verfahren 35 3.2.8 BCA-Protein Assay 36 3.2.9 Versuchsaufbau Einfluss von IGFBP3 auf die Chemosensitivität 37 3.2.10 LDH-Test 37 3.2.11 MTT-Test 38 3.2.12 Bildaufnahmen und Statistische Auswertung 38 4 ERGEBNISSE 39 4.1 Nachweis der Produktion von IGFBP3 39 4.2 Verminderung von freiem IGF-1 nach Überexpression von IGFBP3 41 4.3 Einfluss von IGFBP3 auf das Zellwachstum 43 4.3.1 IGFBP3 hat keinen Einfluss auf das 2D – Wachstum 43 4.3.2 IGFBP3 vermindert die 3D - Proliferation 45 4.4 IGFBP3 vermindert die Invasion der Tumorzellen 48 4.5 IGFBP3 hat keinen Einfluss auf die Migration der Tumorzellen 49 4.6 Einfluss von IGFBP3 auf die Bildung von Angiogenesefaktoren VEGF und bFGF 50 4.7 IGFBP3 hemmt die Freisetzung von MMP-1 52 4.8 Einfluss von IGFBP3 auf die Chemosensitivität 53 4.8.1 Einfluss von IGFBP3 auf 2D- Kulturen nach Zugabe von Cisplatin 53 4.8.2 Einfluss von IGFBP3 auf die 3D- Proliferation nach Zugabe von Cisplatin 56 5 DISKUSSION 59 5.1 Überexpression von IGFBP3 und Verminderung von freiem IGF-1 59 5.2 Wachstum (2D und 3D) 60 5.3 Invasion und MMP-1 62 5.4 Migration 63 5.5 Veränderungen bei der Produktion von Angiogenesefaktoren 64 5.6 Veränderungen bei der Chemosensitivität der H1299- Zellen 65 5.7 Therapeutische Bedeutung von IGFBP3 bei NSCLC 67 6 ZUSAMMENFASSUNG 70 7 LITERATURVERZEICHNIS 73 8 ABBILDUNGSVERZEICHNIS 75 9 TABELLENVERZEICHNIS 75 10 SELBSTSTÄNDIGKEITSERKLÄRUNG 76 11 LEBENSLAUF 77 12 DANKSAGUNG 78
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- 2018
207. Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: Report of five cases.
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Keyszer, Gernot, Christopeit, Maximilian, Fick, Sylvia, Schendel, Marit, Taute, Bettina Maria, Behre, Gerhard, Müller, Lutz Peter, and Schmoll, Hans-Joachim
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SYSTEMIC scleroderma , *STEM cell transplantation , *ANALYSIS of variance , *CONFIDENCE intervals , *HOMOGRAFTS , *HEALTH outcome assessment , *STEM cells , *TREATMENT effectiveness , *THERAPEUTICS - Abstract
The article reports data of five patients with severe progressive systemic sclerosis (SSc) who underwent mesenchymal stromal cells (MSC) transplantation from allogeneic related donors. Details related to the characteristics of the patients in are provided along with factors monitored after the transplant. It was concluded that while MSC transplantation seems promising for patients with refractory autoimmune disease, the phase II trials for patients with severe SSc are necessary.
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- 2011
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208. Cytogenetics detects infiltrations of a primary cutaneous acute myeloid leukemia to the kidney.
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Christopeit, Maximilian, Mueller, Lutz Peter, Hainz, Michael, Holzhausen, Hans-Jürgen, and Behre, Gerhard
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ACUTE myeloid leukemia , *RENAL cancer , *HISTOLOGY , *TOMOGRAPHY , *IN situ hybridization , *CYTOGENETICS - Abstract
Extramedullary manifestations of acute myeloid leukemia (AML) are rare and commonly involve one tissue. We report of a cutaneous acute myelomonocytic leukemia infiltrating the kidney next to the skin. A 61-year-old female patient with complex karyotype cutaneous AML FAB M4 underwent abdominal computed tomography scans. A lesion in her left kidney appeared suspicious of renal carcinoma as confirmed by histology. However, fluorescence in situ hybridization cytogenetics revealed a chromosome 11q23 abnormality in the nephrectomy specimen, which also appeared in the leukemic blasts of skin and bone marrow. Closer histomorphologic workup revealed an infiltration of the kidney with leukemia. This case report illustrates how modern diagnostic procedures can help to reveal rare sites of disease. [ABSTRACT FROM AUTHOR]
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- 2007
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209. Die Telomerlänge als Prognosefaktor in MYCN nicht-amplifizierten Neuroblastomen
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Schulze, Franziska, Christiansen, Holger, Behre, Gerhard, Pfäffle, Roland, and Klinik für Kinder - und Jugendmedizin der Universität Leipzig
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Neuroblastom, Telomere ,ddc:610 ,Neuroblastoma, telomeres - Abstract
Eines der charakteristischen Merkmale des Neuroblastoms stellt seine einzigartige biologische Heterogenität dar, die eine genaue Ausage des weiteren klinischen Verlaufes stark erschwert. Bestimmte prognostisch wirksame klinische, molekularbiologische und genetische Faktoren, wie zum Beispiel Alter bei Erstdiagnose, Tumorstadium, MYCN-Amplifikation und 1p Deletion, werden seit längerem zur Risikostratifizierung genutzt. Bereits in anderen Tumorerkrankungen konnte nun der Einfluß einer Telomerlängenveränderung auf das Gesamtüberleben von Patienten nachgewiesen werden. Telomere sichern die genomische Integrität und bestimmen maßgeblich die proliferative Kapazität jeder somatischen Zelle. Aktuelle Forschungsergebnisse legen die Vermutung nahe, dass Veränderungen der Telomerlänge auch in Neuroblastomen einen prognostischen Effekt auf das Gesamtüberleben haben. In diesem Kontext untersucht die vorliegende Arbeit den Zusammenhang zwischen Telomerlänge und Gesamtüberleben in 420 MYCN nicht-amplifizierten primären Neuroblastomen mit Erstdiagnosen von 1983-2001. Hierfür wurden die relativen Telomerlängen mithilfe einer neu etablierten monochromen multiplex q-RT-PCR ermittelt. Anschließend wurden diese sowohl mit ausgesuchten klinischen Variablen (Alter bei Erstdiagnose, Tumorstadium, Primärlokalisation des Tumors, Histologie, Geschlecht und Rezidivauftreten) korreliert als auch auf ihren Einfluß auf das Gesamt- und ereignisfreie Überleben untersucht. In Korrelation mit den klinischen Parametern konnte zwischen Alter bei Erstdiagnose und Telomerlänge ein eindeutiger Zusammenhang nachgewiesen werden. Je älter die Patienten bei Erstdiagnose, desto höher war sowohl der Anteil verlängerter Telomere als auch der extremer Telomerlängenveränderungen. Neuroblastome mit verlängerten Telomeren zeigten in der gleichen Altersgruppe ein verringertes Gesamtüberleben der betroffenen Patienten verglichen mit Neuroblastomen mit verkürzten Telomeren. Somit könnte eine Telomerlängenveränderung, insbesondere verlängerte Telomere, im klinischen Alltag als Hinweis auf einen prognostisch ungünstigen Verlauf genutzt werden.
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- 2015
210. Klinischer Nutzen von Abdomensonographie und Leberelastographie zur Prädiktion und Diagnostik von Komplikationen bei allogener Stammzelltransplantation
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Kunde, Jacqueline, Karlas, Thomas, Keim, Volker, Kahn, Thomas, Behre, Gerhard, and Universität Leipzig
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acoustic radiation force impulse elastography, transiente Elastography, sonography, allogenic heamatopoietic stem cell transplantation ,Acoustic radiation force Impulse Elastographie, Transiente Elastographie ,Sonographie, allogene Stammzelltransplantation ,ddc:610 - Abstract
Die vorliegende medizinische Dissertation untersucht nicht-invasive bildgebende Verfahren wie die konventionelle Sonographie, die Acoustic radiation force impulse (ARFI)-Elastographie sowie die Transiente Elastographie (TE) zur Detektion von Komplikationen in der Frühphase nach allogener Stammzelltransplantation. Dem kurativen Therapieansatz der Stammzelltransplantation steht ein hohes Komplikationspotential gegenüber. Besonders hepatobiliär treten Graft-versus-host Erkrankungen (GvHD) sowie Gefäßkomplikationen (VOD) auf. Der bisherige diagnostische Goldstandard, die Leberbiopsie, ist als invasives Verfahren mit einer hohen Intra- und Inter-Untersucher-Variabilität sowie der geringen Repräsentativität als Screeningmethode ungeeignet. Die Elastographieverfahren ARFI und TE als nicht-invasive Alternativen ermitteln die Lebergewebesteifigkeit als Surrogatparameter fibrotischer Veränderungen und wurden bereits in zahlreichen Studien als geeignete Diagnoseverfahren für Leberfibrose und -zirrhose unterschiedlicher Ätiologie definiert. Ziel dieser prospektiven Pilotstudie war die Evaluation der genannten Methoden zur Detektion von Frühkomplikationen nach allogener Stammzelltransplantation. Die Ergebnisse der Studie zeigen, dass sowohl die konventionelle Sonographie als auch die Transiente Elastographie pathologische Organveränderungen vor allem des hepatobiliären Systems detektieren können. Allerdings erscheinen diese Veränderungen unspezifisch. Es bestehen keine signifikanten Unterschiede zwischen Patienten mit und ohne Komplikationen. Anders bei der ARFI-Elastographie. Hier zeigten die Messwerte im linken Leberlappen signifikant höhere Werte bei Patienten mit Komplikationen. Zusammenfassend ist die ARFI-Elastographie zur Prädiktion möglicher Komplikationen nach allogener Stammzelltransplantation geeignet, sollte allerdings mit anderen diagnostischen Verfahren ergänzt werden.:III. Inhaltsverzeichnis I. Vorbemerkungen 2 II. Bibliographische Beschreibung 3 III. Inhaltsverzeichnis 4 IV. Abkürzungsverzeichnis 5 1. Einleitung 1.1. Hämatopoetische Stammzelltransplantation 6 2. Komplikationen nach allogener Stammzelltransplantation und deren Diagnostik 2.1. Akute Komplikationen 8 2.2. Akute und chronische Graft-versus-host Erkrankung 9 2.3. Hepatobiliäre Komplikationen 12 2.3.1. Veno-occlusive disease 12 2.3.2. Drug-induced liver injury 14 2.3.3. Problematik der Diagnostik 16 3. Risikostratifizierung bei Stammzelltransplantation 16 3.1. Karnovsky Index und Eastern Cooperative Oncology Group Index 16 3.2. Hematopoietic cell transplantation comorbidity index 17 3.3. Leberspezifisches Risikoassessment 18 4. Nicht-invasive Leberdiagnostik 19 4.1. Konventionelle Sonographie 19 4.2. Elastographie 20 4.2.1. Transiente Elastographie 21 4.2.2. Acoustic radiation force impulse imaging 22 5. Prospektive Studie: Sonographische Evaluation von Komplikationen in der Frühphase nach allogener Stammzelltransplantation 23 5.1. Methodik 24 5.2. Eigener Arbeitsanteil 24 6. Publikationsmanuskript 25 7. Zusammenfassung 32 8. Literaturverzeichnis 36 9. Selbständigkeitserklärung 44 10. Lebenslauf 45 11. Danksagung 46
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- 2015
211. INHIBITION MYCN- VERMITTELTER ZELLZYKLUSTRANSITION DURCH THYROID CANCER 1 (TC1) IM NEUROBLASTOM – ETABLIERUNG UND CHARAKTERISIERUNG DES TC1- ÜBEREXPRESSIONSPHÄNOTYPS IN HUMANEN SH-EP NEUROBLASTOMZELLEN UNTER DEM EINFLUSS VON MYCN
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Weiher, Moritz Adrian, Christiansen, Holger, Starke, Sven, Thóme, Ulrich H., Behre, Gerhard, and Universität Leipzig
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Neuroblastom, MYCN, Thyroid Cancer 1, TC1, C8orf4 ,Neuroblastoma, MYCN, Thyroid Cancer 1, TC1, C8orf4 ,ddc:610 - Abstract
Das Neuroblastom ist der dritthäufigste maligne Tumor im Kindesalter und ist für 15% der Todesfälle durch Krebs bei Kindern unter 14 Jahren verantwortlich. Viele molekularbiologische Vorgänge, die zu der heterogenen Prognose der Patienten beitragen, sind noch nicht verstanden. Als Hauptrisikomerkmal stellt sich die Amplifikation und erhöhte Expression von MYCN dar. In Vorarbeiten der Arbeitsgruppe von Prof. Christiansen zeigte MYCN Einfluss auf die Genregion von Thyroid Cancer 1 (TC1), das als neuer Marker für maligne Schilddrüsenkarzinome erkannt wurde. In der vorliegenden Arbeit wurden erste Untersuchungen zur prognostischen Bedeutung von TC1 im Neuroblastom, sowie die Charakterisierung eines TC1 Überexpressionsphänotyps humaner Neuroblastomzelllinien unter Einfluss von MYCN durchgeführt. Es wurde ein Überexpressionsvektor von TC1 in die Neuroblastomzelllinie SH-EP eingebracht, welche über ein aktivierbares MYCN- Konstrukt verfügt. Dieser neue Phänotyp wurde bezüglich der Proliferation, des Zellzyklus und der Apoptose im Vergleich zu einer Kontrollzelllinie ohne Überexpression untersucht. Eine In-silico Recherche in der Versteeg Neuroblastomdatenbank ergab eine deutlich bessere Überlebenswahrscheinlichkeit für Patientin mit hoher TC1 Expression. Es konnte gezeigt werden, dass MYCN Amplifikation und Expression in einem Panel von Neuroblastom Zelllinien nicht mit der TC1 Expression korrelieren. Die spezifische Aktivierung von MYCN führte hingegen zu einer Expressionssteigerung von TC1. Weiterhin zeigte sich, dass eine TC1 Überexpression die Proliferation hemmt, indem es die MYCN induzierte G1- S- Phasen- Transition inhibiert. TC1 zeigt antiproliferative Eigenschaften im Zellkulturmodell und stellt sich als neuer prognostisch günstiger Parameter im Neuroblastom dar.
- Published
- 2015
212. Pyrosequenzierungsbasierte Analyse von SNP-Loci zur Diagnostik des Heterozygotieverlust auf Chromosom 3 im uvealen malignen Melanom
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Hartig, Andreas, Wickenhauser, Claudia, Müller, Wolf Christoph, Behre, Gerhard, and Universität Leipzig
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uveal melanoma, pyrosequencing ,uveales malignes Melanom, Pyrosequenzierung ,ddc:610 - Abstract
Im Rahmen der Dissertation wurde ein Verfahren zur Quantifizierung monosomer Zellpopulationen innerhalb eines disomen Normalgewebes auf Basis der Pyrosequenzierung von Einzelbasenmutationen etabliert und hinsichtlich seiner Genauigkeit untersucht. Dabei liegt ein besonderer Schwerpunkt auf der Entwicklung eines Verfahrens zur Festlegung von Grenzwerten für die Detektion monosomer Population sowie für genetisch heterogene Subpopulationen. Zur Bestimmung der Genauigkeit wurden Mischreihen von DNA zweier Genotypen angefertigt und das Allelverhältnis durch Pyrosequenzierung gemessen. Diese Ergebnisse wurden genutzt, um Grenzwerte für die Detektion von LOH3-positiven Zellen im UMM estzulegen. In diesen Vorversuchen konnte die Anwendbarkeit der Analysemethode für Proben aus UMM sowohl aus Enukleations wie auch aus Feinnadelaspirationspräparaten demonstriert werden. Es wurde dann in einem weiteren Schritt analysiert, wie viele differente Loci für eine korrekte Diskriminierung zweier Genotypen analysiert werden müssen. Hier wurde gezeigt, dass zum einen die Anzahl der untersuchten SNP aber auch das gemessene Allelverhältnis maßgeblichen Einfluss auf die Genauigkeit der Analyse haben. Basierend auf diesen Daten wurde ein Verfahren entwickelt, das aus der gewünschten Genauigkeit eine Berechnung des Umfangs eines zu etablierenden SNP-Panels ermöglichte.
- Published
- 2015
213. Declined presentation the novel C/EBPalpha target gene EVI2B regulates myeloid differentiation and hematopoietic progenitor cell function.
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Zjablovskaja, Polina, Kardosova, Miroslava, Danek, Petr, Angelisova, Pavla, Benoukraf, Touati, Wurm, Alexander, Kalina, Tomas, Sian, Stephanie, Balastik, Martin, Delwel, Ruud, Brdicka, Tomas, Tenen, Daniel, Behre, Gerhard, Fiore, Fréderic, Malissen, Bernard, Horejsi, Vaclav, and Alberich-Jorda, Meritxell
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HEMATOPOIETIC stem cells , *CELL physiology - Published
- 2017
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214. MicroRNA Expression Patterns Reveal a Role of the TGF-β Family Signaling in AML Chemo-Resistance.
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Reichelt P, Bernhart S, Wilke F, Schwind S, Cross M, Platzbecker U, and Behre G
- Abstract
Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in translation, which are known to play a role in chemo-resistance. To address this, we compared miRNA profiles in paired chemo-sensitive and chemo-resistant subclones of HL60 cells and used a bioinformatics approach to predict affected pathways. From a total of 38 KEGG pathways implicated, TGF-β/activin family signaling was selected for further study. Chemo-resistant HL60 cells showed an increased TGF-β response but were not rendered chemo-sensitive by specific inhibitors. Differential pathway expression in primary AML samples was then investigated at the RNA level using publically available gene expression data in the TGCA database and by longitudinal analysis of pre- and post-resistance samples available from a limited number of patients. This confirmed differential expression and activity of the TGF-β family signaling pathway upon relapse and revealed that the expression of TGF-β and activin signaling genes at diagnosis was associated with overall survival. Our focus on a matched pair of cytarabine sensitive and resistant sublines to identify miRNAs that are associated specifically with resistance, coupled with the use of pathway analysis to rank predicted targets, has thus identified the activin/TGF-β signaling cascade as a potential target for overcoming resistance in AML.
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- 2023
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215. Case report: Allogeneic stem cell transplantation for type B insulin resistance.
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Ebert T, Behre G, Weidhase L, Vucinic V, Gewert C, Semple RK, Stumvoll M, and Tönjes A
- Abstract
Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott-Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ebert, Behre, Weidhase, Vucinic, Gewert, Semple, Stumvoll and Tönjes.)
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- 2023
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216. Characterization of post-vaccination SARS-CoV-2 T cell subtypes in patients with different hematologic malignancies and treatments.
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Pfannes R, Pierzchalski A, Maddalon A, Simion A, Zouboulis CC, Behre G, Zenclussen AC, Westphal S, Fest S, and Herberth G
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- Humans, COVID-19 Vaccines, SARS-CoV-2, Leukocytes, Mononuclear, Herpesvirus 4, Human, Vaccination, Multiple Myeloma, Epstein-Barr Virus Infections, COVID-19 prevention & control, Hematologic Neoplasms therapy
- Abstract
Background: To evaluate the benefits of SARS-CoV-2 vaccination in cancer patients it is relevant to understand the adaptive immune response elicited after vaccination. Patients affected by hematologic malignancies are frequently immune-compromised and show a decreased seroconversion rate compared to other cancer patients or controls. Therefore, vaccine-induced cellular immune responses in these patients might have an important protective role and need a detailed evaluation., Methods: Certain T cell subtypes (CD4, CD8, Tfh, γδT), including cell functionality as indicated by cytokine secretion (IFN, TNF) and expression of activation markers (CD69, CD154) were assessed via multi-parameter flow cytometry in hematologic malignancy patients (N=12) and healthy controls (N=12) after a second SARS-CoV-2 vaccine dose. The PBMC of post-vaccination samples were stimulated with a spike-peptide pool (S-Peptides) of SARS-CoV-2, with CD3/CD28, with a pool of peptides from the cytomegalovirus, Epstein-Barr virus and influenza A virus (CEF-Peptides) or left unstimulated. Furthermore, the concentration of spike-specific antibodies has been analyzed in patients., Results: Our results indicate that hematologic malignancy patients developed a robust cellular immune response to SARS-CoV-2 vaccination comparable to that of healthy controls, and for certain T cell subtypes even higher. The most reactive T cells to SARS-CoV-2 spike peptides belonged to the CD4 and Tfh cell compartment, being median (IQR), 3.39 (1.41-5.92) and 2.12 (0.55-4.14) as a percentage of IFN- and TNF-producing Tfh cells in patients. In this regard, the immunomodulatory treatment of patients before the vaccination period seems important as it was strongly associated with a higher percentage of activated CD4 and Tfh cells. SARS-CoV-2- and CEF-specific T cell responses significantly correlated with each other. Compared to lymphoma patients, myeloma patients had an increased percentage of SARS-CoV-2-specific Tfh cells. T-SNE analysis revealed higher frequencies of γδT cells in patients compared to controls, especially in myeloma patients. In general, after vaccination, SARS-CoV-2-specific T cells were also detectable in patients without seroconversion., Conclusion: Hematologic malignancy patients are capable of developing a SARS-CoV-2-specific CD4 and Tfh cellular immune response after vaccination, and certain immunomodulatory therapies in the period before vaccination might increase the antigen-specific immune response. A proper response to recall antigens (e.g., CEF-Peptides) reflects immune cellular functionality and might be predictive for generating a newly induced antigen-specific immune response as is expected after SARS-CoV-2 vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pfannes, Pierzchalski, Maddalon, Simion, Zouboulis, Behre, Zenclussen, Westphal, Fest and Herberth.)
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- 2023
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217. Effective Extracorporeal Photopheresis of Patients with Transplantation Induced Acute Intestinal GvHD and Bronchiolitis Obliterans Syndrome.
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Reschke R, Zimmerlich S, Döhring C, Behre G, and Ziemer M
- Abstract
Background : Patients with steroid-refractory intestinal acute graft-versus-host disease (aGvHD) and bronchiolitis obliterans syndrome (BOS) represent a population with a high need for alternative and effective treatment options. Methods : We report real-life data from 18 patients treated with extracorporeal photopheresis (ECP). This cohort consisted of nine patients with steroid-refractory intestinal aGvHD and nine patients with BOS. Results : We document partial or complete clinical response and reduction of symptoms in half of the patients with intestinal acute GvHD and patients with BOS treated ECP. Responding patients tended to stay on treatment longer. In patients with BOS, stabilization of lung function and forced expiratory volume was observed, whereas, less abdominal pain, less diarrhea, and a reduction of systemic corticosteroids were seen in patients with intestinal acute GvHD. Conclusions : ECP might not only abrogate symptoms but also reduce mortality caused by complications from high-dose steroid treatment. Taken together, ECP offers a serious treatment avenue for patients with steroid-refractory intestinal acute GvHD and BOS.
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- 2022
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218. Bamlanivimab and Etesevimab Improve Symptoms and Associated Outcomes in Ambulatory Patients at Increased Risk for Severe Coronavirus Disease 2019: Results From the Placebo-Controlled Double-Blind Phase 3 BLAZE-1 Trial.
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Chen P, Behre G, Hebert C, Kumar P, Farmer Macpherson L, Graham-Clarke PL, De La Torre I, Nichols RM, Hufford MM, Patel DR, and Naegeli AN
- Abstract
Background: In the phase 2/3 BLAZE-1 trial, bamlanivimab and etesevimab together reduced coronavirus disease 2019 (COVID-19)-related hospitalizations and any-cause mortality in ambulatory patients. Herein, we assess the impact of bamlanivimab and etesevimab treatment on the severity and length of symptoms and health outcomes among patients at increased risk for severe COVID-19., Methods: In the phase 3 portion of BLAZE-1 (NCT04427501), symptomatic patients with increased risk for severe COVID-19 were randomized (2:1) to a single infusion of 700 mg bamlanivimab and 1400 mg etesevimab or placebo. Hospitalization events, vital signs, and symptomatology were monitored throughout the trial., Results: Overall, 769 patients were randomized to bamlanivimab and etesevimab together (n = 511) or placebo (n = 258). The time to sustained symptom resolution was significantly shorter among patients who received bamlanivimab and etesevimab compared with placebo (8 vs 10 days; P < .01). The median time to first sustained symptom resolution of body aches and pain, chills, fatigue, feeling feverish, headache, and shortness of breath was significantly different in patients receiving bamlanivimab and etesevimab compared to placebo ( P < .05). The proportion of patients who experienced COVID-19-related hospitalization by day 29 was significantly reduced among the bamlanivimab and etesevimab group compared with placebo (0.8% vs 5.4%; P < .01). The mean duration of hospital stay was numerically shorter among patients who received bamlanivimab and etesevimab (7.3 vs 13.5 days; P = .16), with fewer intensive care admissions., Conclusions: Patients receiving bamlanivimab and etesevimab together resolved their symptoms more rapidly than those receiving placebo. Bamlanivimab and etesevimab treatment was associated with reduced rates of hospitalizations and shorter hospital stays., Clinical Trials Registration: NCT04427501., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2022
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219. The tamoxifen-regulated, long non-coding RNA LINC00992 affects proliferation, migration, and expression of tamoxifen resistance-associated genes in MCF-7 breast cancer cells.
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Graf S, Haybaeck J, Behre G, Kalinski T, and Nass N
- Abstract
Introduction: Tamoxifen-adapted MCF-7 breast cancer cells (MCF-7-TAM-R) are a model for acquired tamoxifen resistance in oestrogen receptor-positive breast cancer. In this system, the expression of long-non-coding RNA LINC00992 is decreased. LINC00992 might therefore contribute to tamoxifen adaption and associated gene expres-sion changes. Here, we investigated whether a modulation of LINC00992 modifies gene expression, proliferation, and migration., Material and Methods: Up- and down-- regulation of LINC00992 was performed using plasmid vectors and siRNA. Gene expression was measured via nCounter® and quantitative real-time polymerase chain reaction. Database analysis was performed using GEPIA2 and cBioportal. Furthermore, we performed scratch assays, colony-forming assays, and proliferation assays with MCF-7 and MCF-7-TAM-R after up-regulation of LINC00992., Results: Up- and down-regulation of LINC00992 caused gene expression changes in 4 of the 42 tamoxifen-regulated genes tested. Especially ubiquitin D, single-minded homologue 1 (SIM1) carcinoembryonic antigen-related cell adhesion molecule 5 and the G-protein coupled oestrogen receptor 1 were affected. In tamoxifen-adapted MCF-7-TAM-R cells, LINC00992 overexpression resulted in augmented viability and proliferation and enhanced migration. Database analyses revealed that luminal breast cancers have increased expression of LINC00992 compared to Her2-type/neu- or basal type. Furthermore, higher expression of LINC00992 was associated with poor prognosis in luminal-A carcinomas., Conclusions: Changes in the expression of tamoxifen-regulated genes could be induced by manipulating LINC00992's abundance, suggesting that it is at least partially involved in the establishment of the tamoxifen-induced gene expression pattern. LINC00992 may also serve as a prognostic biomarker and may indicate the development of tamoxifen resistance., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)
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- 2022
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220. High expression of the stem cell marker GPR56 at diagnosis identifies acute myeloid leukemia patients at higher relapse risk after allogeneic stem cell transplantation in context with the CD34+/CD38- population.
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Jentzsch M, Bill M, Grimm J, Schulz J, Schuhmann L, Brauer D, Goldmann K, Wilke F, Franke GN, Behre G, Pönisch W, Vucinic V, Niederwieser D, Platzbecker U, and Schwind S
- Subjects
- ADP-ribosyl Cyclase 1, Antigens, CD34, Humans, Neoplastic Stem Cells, Receptors, G-Protein-Coupled, Recurrence, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
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- 2020
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221. Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible.
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Vucinic V, Jentzsch M, Schwind S, Bach E, Leiblein S, Remane Y, Rieprecht S, Otto S, Kubasch AS, Behre G, Cross M, Platzbecker U, and Franke GN
- Abstract
Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and treatment-related acute myeloid leukemia (tAML) after chemotherapy or radiation therapy for other neoplasms are associated with poor outcomes. CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, has been shown to improve outcomes in AML-MRC and tAML compared with standard 7+3 regimens. Here we report the cases of four consecutive patients with AML-MRC or tAML who received CPX-351 as outpatient induction therapy immediately followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two patients received allo-HSCT in remission (one in complete remission and one in partial remission) and two patients received allo-HSCT in aplasia (one at 11 days and one at 52 days after the start of induction therapy with CPX-351). With a median follow-up of 188 days after allo-HSCT, all but one patient are alive and two are in remission. Further studies will help define and expand the role of CPX-351 in the treatment of AML-MRC and tAML, especially in patients expected to undergo allo-HSCT., (Copyright © 2020 Vucinic, Jentzsch, Schwind, Bach, Leiblein, Remane, Rieprecht, Otto, Kubasch, Behre, Cross, Platzbecker and Franke.)
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- 2020
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222. Allogeneic Hematopoietic Stem Cell Transplantation in a Rare Case of Tonsillar Mast Cell Sarcoma.
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Kubasch AS, Franke GN, Aldaoud A, Weibl K, Jentzsch M, Sabri O, Horny HP, Fend F, Behre G, Platzbecker U, and Vucinic V
- Abstract
Mast cell sarcoma comprises a rare aggressive mast cell neoplasia with histological, clinical, and genetic features distinct from other mast cell neoplasm. Until now, prognosis is still poor due to high rates of progression to mast cell leukemia and failure of conventional chemotherapies. Our here presented first report about successful allogeneic hematopoietic stem cell transplantation leading to remission in a case of tonsillar MCS represents a promising potential curative treatment option for this rare and often fatal disease., (Copyright © 2020 Kubasch, Franke, Aldaoud, Weibl, Jentzsch, Sabri, Horny, Fend, Behre, Platzbecker and Vucinic.)
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- 2020
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223. Comparison of non-myeloablative and reduced-intensity allogeneic stem cell transplantation in older patients with myelodysplastic syndromes.
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Jentzsch M, Döhring C, Linke R, Hille A, Grimm J, Pönisch W, Vucinic V, Franke GN, Behre G, Niederwieser D, and Schwind S
- Subjects
- Age Factors, Aged, Aged, 80 and over, Busulfan administration & dosage, Busulfan adverse effects, Busulfan analogs & derivatives, Comorbidity, Graft vs Host Disease prevention & control, Humans, Immunosuppressive Agents therapeutic use, Kaplan-Meier Estimate, Middle Aged, Myeloablative Agonists administration & dosage, Myeloablative Agonists adverse effects, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes therapy, Myeloproliferative Disorders epidemiology, Myeloproliferative Disorders therapy, Proportional Hazards Models, Recurrence, Retrospective Studies, Transplantation Conditioning adverse effects, Treatment Outcome, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Whole-Body Irradiation, Peripheral Blood Stem Cell Transplantation adverse effects, Transplantation Conditioning methods
- Abstract
Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non-myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA- or RIC-HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC-HSCT or NMA-HSCT were balanced in factors reflecting disease aggressiveness and the HCT-CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft-vs-host disease. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients <65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients <65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients <65 years may benefit from RIC-HSCT., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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224. Author Correction: Predicting hepatic complications of allogeneic hematopoietic stem cell transplantation using liver stiffness measurement.
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Karlas T, Weiße T, Petroff D, Beer S, Döhring C, Gnatzy F, Niederwieser D, Behre G, Mössner J, Fischer J, Tröltzsch M, Wiegand J, Keim V, and Franke GN
- Abstract
In the original article, the affiliations were presented incorrectly. David Petroff is in fact the only author at affiliation 2. All other authors listed as being at affiliation 2 (Tina Weiße, Sebastian Beer, Franziska Gnatzy, Joachim Mössner, Michael Tröltzsch, Johannes Wiegand and Volker Keim) are in fact just at affiliation 1. These have now been corrected in the original article.
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- 2019
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225. Predicting hepatic complications of allogeneic hematopoietic stem cell transplantation using liver stiffness measurement.
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Karlas T, Weiße T, Petroff D, Beer S, Döhring C, Gnatzy F, Niederwieser D, Behre G, Mössner J, Fischer J, Tröltzsch M, Wiegand J, Keim V, and Franke GN
- Subjects
- Allografts, Disease-Free Survival, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Survival Rate, Elasticity Imaging Techniques, Hematopoietic Stem Cell Transplantation, Liver diagnostic imaging, Liver Diseases diagnostic imaging, Liver Diseases etiology, Liver Diseases mortality
- Abstract
Allogeneic hematopoietic stem cell transplantation is the only curative option for a variety of diseases. Despite advances, it is associated with considerable morbidity and mortality, often involving liver complications. Liver disease can be characterized using ultrasound-based liver stiffness measurement. To assess its prognostic value, consecutive patients undergoing allogeneic hematopoietic stem cell transplantation were prospectively evaluated in a single-center study. Endpoints included liver event-free survival and all-cause mortality at 1 year. Competing risk and Cox-regression were used for analysis. We evaluated 106 patients (42 female, age 57) and observed 33 life-threatening events (14 died) including 16 liver complications at 100 days. At 1 year, 36 patients had died, 20 with disease relapse. The hazard ratios for liver-related complications at 100 days were 3.2 (95% CI: 1.8-14.6, p = 0.0022) and 4.4 (95% CI: 1.6-11.9, p = 0.0042) for elevated transient elastography (n = 11) and shear-wave velocity (n = 31), respectively. Results were analogous for all-cause mortality at 1 year. Prior stem cell therapy and elevated gamma glutamyltransferase were also associated with outcome. This demonstrates that elastography is a promising and viable tool for risk prediction and should be included in upcoming multi-center trials to establish new means of guiding treatment and prophylaxis.
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- 2019
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226. Clinical impact of clonal hematopoiesis in acute myeloid leukemia patients receiving allogeneic transplantation.
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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.
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- 2019
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227. Prognostic Impact of Blood MN1 Copy Numbers Before Allogeneic Stem Cell Transplantation in Patients With Acute Myeloid Leukemia.
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Jentzsch M, Bill M, Grimm J, Schulz J, Beinicke S, Häntschel J, Goldmann K, Pönisch W, Franke GN, Vucinic V, Cross M, Behre G, Lange T, Niederwieser D, and Schwind S
- Abstract
High expression of the leukemia-associated gene meningioma-1 ( MN1 ) is frequently found at diagnosis of acute myeloid leukemia (AML) and associates with adverse outcomes. The presence of measurable residual disease (MRD) in complete remission (CR) indicates high risk of relapse and worse outcome in AML patients. However, the prognostic impact of MN1 expression levels as MRD marker has not been evaluated. Digital droplet polymerase chain reaction (ddPCR) is a novel technique allowing sensitive and specific absolute gene expression quantification. We retrospectively analyzed 124 AML patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in CR or CR with incomplete peripheral recovery. Absolute MN1 copy numbers in peripheral blood were assessed prior to HSCT (median 7; range 0-29 days) using ddPCR. High pre-HSCT MN1 /Abelson murine leukemia viral oncogene homolog 1 gene ( ABL1 ) copy numbers associated with a higher cumulative incidence of relapse after HSCT and-in relapsing patients-shorter time to relapse. In multivariable analysis, high pre-HSCT MN1 / ABL1 copy numbers remained an independent prognosticator for relapse after HSCT. Patients with the highest pre-HSCT MN1 / ABL1 copy numbers also had the highest risk of relapse. MN1 copy number assessment also added prognostic information to nucleophosmin 1 gene ( NPM1 ) mutation- and brain and acute leukemia, cytoplasmic ( BAALC ) and Wilm's tumor gene 1 ( WT1 ) expression-based MRD evaluation. Our study demonstrates the feasibility of the novel ddPCR technique for MN1 / ABL1 copy number assessment as a marker for MRD. Evaluation of MN1 / ABL1 copy numbers allows the identification of patients at high risk of relapse, independently of other diagnostic risk factors and MRD markers., (Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2019
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228. Correction to: 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
- Abstract
Since publication of this article, the authors identified an error in the acknowledgments section. The original sentence in acknowledgments reads as follows.
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- 2019
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229. Diagnosis of invasive fungal diseases in haematology and oncology: 2018 update of the recommendations of the infectious diseases working party of the German society for hematology and medical oncology (AGIHO).
- Author
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Ruhnke M, Behre G, Buchheidt D, Christopeit M, Hamprecht A, Heinz W, Heussel CP, Horger M, Kurzai O, Karthaus M, Löffler J, Maschmeyer G, Penack O, Rieger C, Rickerts V, Ritter J, Schmidt-Hieber M, Schuelper N, Schwartz S, Ullmann A, Vehreschild JJ, von Lilienfeld-Toal M, Weber T, and Wolf HH
- Subjects
- Antifungal Agents therapeutic use, Fungi genetics, Fungi isolation & purification, Fungi physiology, Germany, Hematology, Humans, Invasive Fungal Infections drug therapy, Invasive Fungal Infections microbiology, Medical Oncology, Practice Guidelines as Topic, Invasive Fungal Infections diagnosis
- Abstract
Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions., (© 2018 Blackwell Verlag GmbH.)
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- 2018
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230. 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.
- Author
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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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231. Efficacy and safety of keratinocyte growth factor (palifermin) for prevention of oral mucositis in TBI-based allogeneic hematopoietic stem cell transplantation.
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Schmidt V, Niederwieser D, Schenk T, Behre G, Klink A, Pfrepper C, Hinke A, Beelen DW, Junghanss C, Uharek L, Krüger WH, Hochhaus A, and Sayer HG
- Subjects
- Adult, Female, Fibroblast Growth Factor 7 therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Male, Middle Aged, Transplantation, Homologous, Treatment Outcome, Whole-Body Irradiation, Young Adult, Fibroblast Growth Factor 7 administration & dosage, Hematopoietic Stem Cell Transplantation methods, Stomatitis prevention & control
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- 2018
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232. MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia.
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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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233. Prognostic relevance of DNMT3A R882 mutations in AML patients undergoing non-myeloablative conditioning hematopoietic stem cell transplantation.
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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
- Subjects
- 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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234. miR-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia.
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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
- Full Text
- View/download PDF
235. ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia.
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Namasu CY, Katzerke C, Bräuer-Hartmann D, Wurm AA, Gerloff D, Hartmann JU, Schwind S, Müller-Tidow C, Hilger N, Fricke S, Christopeit M, Niederwieser D, and Behre G
- Abstract
Active BCR related ( ABR ) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia. BCR gene, closely related to ABR, acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with ABR . Evidence for a putative tumor suppressor role of ABR has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of ABR in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPα, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPα in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high ABR expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that ABR expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of ABR and underline its potential role in leukemia therapeutic strategies., Competing Interests: CONFLICTS OF INTEREST None.
- Published
- 2017
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236. High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia patients.
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Jentzsch M, Bill M, Grimm J, Schulz J, Goldmann K, Beinicke S, Häntschel J, Pönisch W, Franke GN, Vucinic V, Behre G, Lange T, Niederwieser D, and Schwind S
- Abstract
High BAALC expression levels at acute myeloid leukemia diagnosis have been linked to adverse outcomes. Recent data indicate that high BAALC expression levels may also be used as marker for residual disease following acute myeloid leukemia treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment for acute myeloid leukemia patients. However, disease recurrence remains a major clinical challenge and identification of high-risk patients prior to HSCT is crucial to improve outcomes. We performed absolute quantification of BAALC copy numbers in peripheral blood prior (median 7 days) to HSCT in complete remission (CR) or CR with incomplete peripheral recovery in 82 acute myeloid leukemia patients using digital droplet PCR (ddPCR) technology. An optimal cut-off of 0.14 BAALC / ABL1 copy numbers was determined and applied to define patients with high or low BAALC / ABL1 copy numbers. High pre-HSCT BAALC / ABL1 copy numbers significantly associated with higher cumulative incidence of relapse and shorter overall survival in univariable and multivariable models. Patients with high pre-HSCT BAALC / ABL1 copy numbers were more likely to experience relapse within 100 days after HSCT. Evaluation of pre-HSCT BAALC / ABL1 copy numbers in peripheral blood by ddPCR represents a feasible and rapid way to identify acute myeloid leukemia patients at high risk of early relapse after HSCT. The prognostic impact was also observed independently of other known clinical, genetic, and molecular prognosticators. In the future, prospective studies should evaluate whether acute myeloid leukemia patients with high pre-HSCT BAALC / ABL1 copy numbers benefit from additional treatment before or early intervention after HSCT., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
- Published
- 2017
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237. Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma.
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Pönisch W, Holzvogt B, Plötze M, Andrea M, Bourgeois M, Heyn S, Zehrfeld T, Hammerschmidt D, Schwarz M, Edelmann T, Becker C, Hoffmann FA, Schwarzer A, Kreibich U, Gutsche K, Reifenrath K, Winkelmann C, Krahl R, Remane Y, Hennig E, Schliwa T, Lindner T, Kaiser T, Vucinic V, Behre G, and Niederwieser D
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride, Boronic Acids administration & dosage, Bortezomib, Disease-Free Survival, Female, Glomerular Filtration Rate, Humans, Kaplan-Meier Estimate, Leukopenia chemically induced, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma physiopathology, Nitrogen Mustard Compounds administration & dosage, Prednisone administration & dosage, Pyrazines administration & dosage, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Abstract
Introduction: Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM., Methods: Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥ 60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15-59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min)., Results: A median number of two (range 1-5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively. These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.
- Published
- 2014
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238. Proteomic analysis of rosiglitazone and guggulsterone treated 3T3-L1 preadipocytes.
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Pal P, Kanaujiya JK, Lochab S, Tripathi SB, Sanyal S, Behre G, and Trivedi AK
- Subjects
- 3T3-L1 Cells drug effects, 3T3-L1 Cells metabolism, Adipogenesis drug effects, Animals, Annexin A2 genetics, Annexin A2 metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Electrophoresis, Gel, Two-Dimensional methods, Galectin 1 genetics, Galectin 1 metabolism, Mice, Real-Time Polymerase Chain Reaction, Rosiglitazone, Tumor Protein, Translationally-Controlled 1, Adipocytes drug effects, Adipocytes metabolism, Hypoglycemic Agents pharmacology, Pregnenediones pharmacology, Proteomics methods, Thiazolidinediones pharmacology
- Abstract
Adipogenesis is the differentiation of preadipocytes to adipocytes which is marked by the accumulation of lipid droplets. Adipogenic differentiation of 3T3-L1 cells is achieved by exposing the cells to Insulin, Dexamethasone and IBMX for 5-7 days. Thiazolidinedione drugs, like rosiglitazone are potent insulin sensitizing agents and have been shown to enhance lipid droplet formation in 3T3-L1 cells, a model cell line for preadipocyte differentiation. Guggulsterone is a natural drug extracted from the gum resin of tree Commiphora mukul. Guggulsterone has been shown to inhibit adipogenesis and induce apoptosis in 3T3-L1 cells. In this study we treated the 3T3-L1 preadipocytes with rosiglitazone and guggulsterone and assessed the protein expression profile using 2D gel electrophoresis-based proteomics to find out differential target proteins of these drugs. The proteins that were identified upon rosiglitazone treatment generally regulate cell proliferation and/or exhibit anti-inflammatory effect which strengthens its differentiation-inducing property. Guggulsterone treatment resulted in the identification of the apoptosis-inducing proteins to be up regulated which rightly is in agreement with the apoptosis-inducing property of guggulsterone in 3T3-L1 cells. Some of the proteins identified in our proteomic screen such as Galectin1, AnnexinA2 & TCTP were further confirmed by Real Time qPCR. Thus, the present study provides a better outlook of proteins being differentially regulated/expressed upon treatment with rosiglitazone and guggulsterone. The detailed study of the differentially expressed proteins identified in this proteomic screen may further provide the better molecular insight into the mode of action of these anti-diabetic drugs rosiglitazone and guggulsterone.
- Published
- 2013
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239. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study.
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Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, Stuhler G, Stelljes M, Schwerdtfeger R, Christopeit M, Behre G, Faul C, Vogel W, Schumm M, Handgretinger R, Kanz L, and Bethge WA
- Subjects
- Adult, Aged, Antigens, CD34, Chimerism, Female, Graft Survival, Graft vs Host Disease, Haplotypes, Hematologic Diseases mortality, Hematopoietic Stem Cells metabolism, Humans, Leukemia therapy, Lymphoma, Non-Hodgkin therapy, Major Histocompatibility Complex genetics, Male, Middle Aged, Multiple Myeloma therapy, Myelodysplastic Syndromes therapy, Receptors, KIR immunology, Risk Factors, Tissue Donors, Transplantation, Homologous, Treatment Outcome, Young Adult, Antigens, CD19, CD3 Complex, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation adverse effects, Lymphocyte Depletion, Transplantation Conditioning
- Abstract
Background: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3., Design and Methods: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (≥ 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 × 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 × 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 × 10(7) (range 0.00-37.3) CD56(+) cells/kg., Results: Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 × 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 × 10(9) (range 7-38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively., Conclusions: This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917).
- Published
- 2012
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240. 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.
- Published
- 2010
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241. 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
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242. Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip.
- Author
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Hoemme C, Peerzada A, Behre G, Wang Y, McClelland M, Nieselt K, Zschunke M, Disselhoff C, Agrawal S, Isken F, Tidow N, Berdel WE, Serve H, and Müller-Tidow C
- Subjects
- Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genome, Human genetics, Histones metabolism, Humans, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Oncogene Proteins, Fusion genetics, Promoter Regions, Genetic genetics, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, U937 Cells, Chromatin metabolism, Chromatin Immunoprecipitation, Leukemia genetics, Leukemia pathology, Oncogene Proteins, Fusion metabolism
- Abstract
The translocation t(15;17) generates the chimeric PML-RARalpha transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARalpha transcriptional functions was obtained by genome-wide binding and chromatin modification analyses combined with genome-wide expression data. Chromatin immunoprecipitation (ChIP)-chip experiments identified 372 direct genomic PML-RARalpha targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARalpha targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell-cycle control and apoptosis. PML-RARalpha binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RARalpha to target promoters and the resulting histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RARalpha regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.
- Published
- 2008
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243. The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate.
- Author
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Schuster C, Forster K, Dierks H, Elsasser A, Behre G, Simon N, Danhauser-Riedl S, Hallek M, and Warmuth M
- Subjects
- Animals, Benzamides, CCAAT-Enhancer-Binding Proteins drug effects, Carrier Proteins metabolism, Cell Differentiation drug effects, Cell Line, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclins metabolism, Drug Antagonism, Fusion Proteins, bcr-abl pharmacology, Gene Expression Regulation, Neoplastic, Granulocyte Colony-Stimulating Factor pharmacology, Granulocytes cytology, Granulocytes drug effects, Imatinib Mesylate, Mice, Neutrophils cytology, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism, Antineoplastic Agents pharmacology, CCAAT-Enhancer-Binding Proteins metabolism, Enzyme Inhibitors pharmacology, Fusion Proteins, bcr-abl drug effects, Intracellular Signaling Peptides and Proteins, Neutrophils drug effects, Piperazines pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine-kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)-induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule-1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein-alpha [C/EBPalpha], C/EBPepsilon, and PU.1), and of the cyclin-dependent kinase inhibitor p27(Kip1). In 32Dcl3 cells transfected with the bcr-abl gene (32D(Bcr-Abl)), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPalpha, C/EBPepsilon, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27(Kip1) by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32D(Bcr-Ablwt) cells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPalpha and C/EBPepsilon expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPalpha and C/EBPepsilon.
- Published
- 2003
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244. Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
- Author
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Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, and Tenen DG
- Subjects
- Acute Disease, Binding Sites genetics, Cell Differentiation genetics, DNA Mutational Analysis, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Granulocytes cytology, Heterozygote, Humans, Leukemia, Myeloid etiology, Leukemia, Myeloid pathology, Leukocytes, Mononuclear pathology, Protein Binding genetics, Proto-Oncogene Proteins pharmacology, Proto-Oncogene Proteins physiology, Receptor, Macrophage Colony-Stimulating Factor genetics, Receptor, Macrophage Colony-Stimulating Factor metabolism, Trans-Activators pharmacology, Trans-Activators physiology, Leukemia, Myeloid genetics, Mutation, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. We identified 10 mutant alleles of the PU.1 gene in 9 of 126 AML patients. The PU.1 mutations comprised 5 deletions affecting the DNA-binding domain, and 5 point mutations in 1) the DNA-binding domain (2 patients), 2) the PEST domain (2 patients), and 3) the transactivation domain (one patient). DNA binding to and transactivation of the M-CSF receptor promoter, a direct PU.1 target gene, were deficient in the 7 PU.1 mutants that affected the DNA-binding domain. In addition, these mutations decreased the ability of PU.1 to synergize with PU.1-interacting proteins such as AML1 or c-Jun in the activation of PU.1 target genes. This is the first report of mutations in the PU.1 gene in human neoplasia and suggests that disruption of PU.1 function contributes to the block in differentiation found in AML patients.
- Published
- 2002
- Full Text
- View/download PDF
245. Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248.
- Author
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Behre G, Singh SM, Liu H, Bortolin LT, Christopeit M, Radomska HS, Rangatia J, Hiddemann W, Friedman AD, and Tenen DG
- Subjects
- Acute Disease, Alanine metabolism, Amino Acid Substitution, CCAAT-Enhancer-Binding Protein-alpha genetics, Cell Differentiation drug effects, Cell Line, Humans, Leukemia, Myeloid metabolism, Phosphorylation, Point Mutation, Promoter Regions, Genetic, Protein Kinase C metabolism, Receptors, Granulocyte Colony-Stimulating Factor genetics, Signal Transduction, Transcriptional Activation, CCAAT-Enhancer-Binding Protein-alpha metabolism, Granulocytes cytology, Serine metabolism, ras Proteins physiology
- Abstract
The transcription factor C/EBP alpha regulates early steps of normal granulocyte differentiation since mice with a disruption of the C/EBP alpha gene do not express detectable levels of the granulocyte colony-stimulating factor receptor and produce no neutrophils. We have recently shown that C/EBP alpha function is also impaired in acute myeloid leukemias. However, how the transcriptional activity of C/EBP alpha is regulated both in myelopoiesis and leukemogenesis is not fully understood. The current study demonstrates that activated Ras enhances the ability of C/EBP alpha to transactivate the granulocyte colony-stimulating factor receptor promoter and a minimal promoter containing only C/EBP DNA binding sites. Ras signaling activates C/EBP alpha via the transactivation domain because it enhances the transactivation function of a fusion protein containing a Gal4 DNA binding domain and the C/EBP alpha transactivation domain and does not change C/EBP alpha DNA binding. Ras acts on serine 248 of the C/EBP alpha transactivation domain, because it does not enhance the transactivation function of a C/EBP alpha serine 248 to alanine point mutant. Interestingly, serine 248 of C/EBP alpha is a protein kinase C (PKC) consensus site, and a PKC inhibitor blocks the activation of C/EB alpha by Ras. Ras signaling leads to phosphorylation of C/EBP alpha in vivo. Finally, mutation of serine 248 to alanine obviates the ability of C/EBP alpha to induce granulocytic differentiation. These data suggest a model where Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248.
- Published
- 2002
- Full Text
- View/download PDF
246. Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions.
- Author
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Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK, Tenen DG, Hiddemann W, and Behre G
- Subjects
- Animals, Binding Sites, CCAAT-Enhancer-Binding Protein-alpha pharmacology, Cell Line, Cell Lineage drug effects, Fetal Blood cytology, Hematopoiesis drug effects, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells drug effects, Humans, Mice, Myeloid Progenitor Cells cytology, Myeloid Progenitor Cells drug effects, Proto-Oncogene Proteins c-jun antagonists & inhibitors, Receptor Cross-Talk, U937 Cells, CCAAT-Enhancer-Binding Protein-alpha physiology, Granulocytes cytology, Proto-Oncogene Proteins antagonists & inhibitors, Trans-Activators antagonists & inhibitors
- Abstract
Several transcription factors have been implicated as playing a role in myelopoiesis. PU.1, an ets-family transcription factor, is required for the development of myeloid and lymphoid lineages, whereas the transcription factor CCAAT-enhancer binding protein family member C/EBPalpha is essential for granulocyte development. We present here the first evidence that C/EBPalpha blocks the function of PU.1. PU.1 and C/EBPalpha interact physically and colocalize in myeloid cells. As a consequence of this interaction, C/EBPalpha can inhibit the function of PU.1 to activate a minimal promoter containing only PU.1 DNA-binding sites. We further demonstrate that the leucine zipper in the DNA-binding domain of C/EBPalpha interacts with the beta3/beta4 region in the DNA-binding domain of PU.1 and as a result displaces the PU.1 coactivator c-Jun. Finally, C/EBPalpha blocks PU.1-induced dendritic cell development from CD34+ human cord blood cells. The functional blocking of PU.1 by C/EBPalpha could be the mechanism by which C/EBPalpha inhibits cell fates specified by PU.1 and directs cell development to the granulocyte lineage.
- Published
- 2002
- Full Text
- View/download PDF
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