TY - JOUR A1 - Rauert, H. A1 - Stühmer, T. A1 - Bargou, R. A1 - Wajant, H. A1 - Siegmund, D. T1 - TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms N2 - The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFjBmediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFjB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival. KW - Medizin KW - apoptosis KW - CD95 KW - multiple myeloma KW - NFkB KW - TNF KW - TRAIL Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76092 ER - TY - JOUR A1 - Rauert, H. A1 - Stühmer, T. A1 - Bargou, R. A1 - Wajant, H. A1 - Siegmund, D. T1 - TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms JF - Cell Death and Disease N2 - The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFjBmediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFjB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival KW - apoptosis KW - CD95 KW - multiple myeloma KW - NFkB KW - TNF KW - TRAIL KW - NF-Kappa-B KW - Tumor-necrosis-factor KW - Factor receptor KW - Factor-alpha KW - Activation KW - Polymorphisms KW - Inhibitor KW - Promoter KW - Transcription KW - Expression Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133486 VL - 2 ER - TY - JOUR A1 - Leich, E. A1 - Weißbach, S. A1 - Klein, H.-U. A1 - Grieb, T. A1 - Pischimarov, J. A1 - Stühmer, T. A1 - Chatterjee, M. A1 - Steinbrunn, T. A1 - Langer, C. A1 - Eilers, M. A1 - Knop, S. A1 - Einsele, H. A1 - Bargou, R. A1 - Rosenwald, A. T1 - Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules JF - Blood Cancer Journal N2 - Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient. KW - multiple myeloma KW - somatic mutations KW - whole-exome sequencing KW - adhesion KW - receptor tyrosine kinases Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128663 VL - 3 IS - e102 ER - TY - JOUR A1 - Zugmaier, G. A1 - Topp, M. S. A1 - Alekar, S. A1 - Viardot, A. A1 - Horst, H.-A. A1 - Neumann, S. A1 - Stelljes, M. A1 - Bargou, R. C. A1 - Goebeler, M. A1 - Wessiepe, D. A1 - Degenhard, E. A1 - Goekbuget, N. A1 - Klinger, M. T1 - Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia JF - Blood Cancer Journal N2 - No abstract available. KW - stem-cell transplantation KW - free survival KW - engaging aantibody KW - Rituximab KW - lymphoma KW - hypogammaglobulinemia KW - lineage Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115433 SN - 2044-5385 VL - 4 IS - e244 ER - TY - JOUR A1 - Stein, Anthony S. A1 - Kantarjian, Hagop A1 - Gökbuget, Nicola A1 - Bargou, Ralf A1 - Litzow, Mark R. A1 - Rambaldi, Alessandro A1 - Ribera, Josep-Maria A1 - Zhang, Alicia A1 - Zimmerman, Zachary A1 - Zugmaier, Gerhard A1 - Topp, Max S. T1 - Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation JF - Biology of Blood and Marrow Transplantation N2 - Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population. KW - blinatumomab KW - Philadelphia chromosome-negative B precursor ALL KW - efficacy KW - safety KW - allogeneic hematopoietic stem cell transplantation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239510 VL - 25 ER -