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17 Publications visible to you, out of a total of 17
Transcriptional states of CAR-T infusion relate to neurotoxicity - lessons from high-resolution single-cell SOM expression portraying.
imSAVAR - Immune safety avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies

Abstract (Expand)

Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular … data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient's infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity.

Authors: H. Loeffler-Wirth, M. Rade, A. Arakelyan, M. Kreuz, M. Loeffler, U. Koehl, K. Reiche, H. Binder

Date Published: 17th Oct 2022

Publication Type: Journal article

A modular transcriptome map of mature B cell lymphomas.
GLA - German Lymphoma Alliance, MMML-MYC-SYS, oBIG - omics Bioinformatics for Health

Abstract (Expand)

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.

Authors: H. Loeffler-Wirth, M. Kreuz, L. Hopp, A. Arakelyan, A. Haake, S. B. Cogliatti, A. C. Feller, M. L. Hansmann, D. Lenze, P. Moller, H. K. Muller-Hermelink, E. Fortenbacher, E. Willscher, G. Ott, A. Rosenwald, C. Pott, C. Schwaenen, H. Trautmann, S. Wessendorf, H. Stein, M. Szczepanowski, L. Trumper, M. Hummel, W. Klapper, R. Siebert, M. Loeffler, H. Binder

Date Published: 30th Apr 2019

Publication Type: Not specified

Human Diseases: B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread … genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

Authors: H. Binder, E. Willscher, H. Loeffler-Wirth, L. Hopp, D. T. W. Jones, S. M. Pfister, M. Kreuz, D. Gramatzki, E. Fortenbacher, B. Hentschel, M. Tatagiba, U. Herrlinger, H. Vatter, J. Matschke, M. Westphal, D. Krex, G. Schackert, J. C. Tonn, U. Schlegel, H. J. Steiger, W. Wick, R. G. Weber, M. Weller, M. Loeffler

Date Published: 25th Apr 2019

Publication Type: Not specified

Human Diseases: brain glioma

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. … Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Authors: C. Lopez, K. Kleinheinz, S. M. Aukema, M. Rohde, S. H. Bernhart, D. Hubschmann, R. Wagener, U. H. Toprak, F. Raimondi, M. Kreuz, S. M. Waszak, Z. Huang, L. Sieverling, N. Paramasivam, J. Seufert, S. Sungalee, R. B. Russell, J. Bausinger, H. Kretzmer, O. Ammerpohl, A. K. Bergmann, H. Binder, A. Borkhardt, B. Brors, A. Claviez, G. Doose, L. Feuerbach, A. Haake, M. L. Hansmann, J. Hoell, M. Hummel, J. O. Korbel, C. Lawerenz, D. Lenze, B. Radlwimmer, J. Richter, P. Rosenstiel, A. Rosenwald, M. B. Schilhabel, H. Stein, S. Stilgenbauer, P. F. Stadler, M. Szczepanowski, M. A. Weniger, M. Zapatka, R. Eils, P. Lichter, M. Loeffler, P. Moller, L. Trumper, W. Klapper, S. Hoffmann, R. Kuppers, B. Burkhardt, M. Schlesner, R. Siebert

Date Published: 29th Mar 2019

Publication Type: Not specified

Human Diseases: lymphoma, Burkitt lymphoma

TP53 mutation and survival in aggressive B cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 … mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.

Authors: T. Zenz, M. Kreuz, M. Fuge, W. Klapper, H. Horn, A. M. Staiger, D. Winter, H. Helfrich, J. Huellein, M. L. Hansmann, H. Stein, A. Feller, P. Moller, N. Schmitz, L. Trumper, M. Loeffler, R. Siebert, A. Rosenwald, G. Ott, M. Pfreundschuh, S. Stilgenbauer

Date Published: 1st Oct 2017

Publication Type: Journal article

Human Diseases: non-Hodgkin lymphoma, B-cell lymphoma

Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in … DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. (c) 2016 Wiley Periodicals, Inc.

Authors: C. Otto, R. Scholtysik, R. Schmitz, M. Kreuz, C. Becher, M. Hummel, A. Rosenwald, L. Trumper, W. Klapper, R. Siebert, R. Kuppers

Date Published: 30th Jun 2016

Publication Type: Journal article

Human Diseases: diffuse large B-cell lymphoma

Serum BDNF correlates with connectivity in the (pre)motor hub in the aging human brain--a resting-state fMRI pilot study.
LIFE Adult

Abstract (Expand)

Brain-derived neurotrophic factor (BDNF) has been discussed to be involved in plasticity processes in the human brain, in particular during aging. Recently, aging and its (neurodegenerative) diseases … have increasingly been conceptualized as disconnection syndromes. Here, connectivity changes in neural networks (the connectome) are suggested to be the most relevant and characteristic features for such processes or diseases. To further elucidate the impact of aging on neural networks, we investigated the interaction between plasticity processes, brain connectivity, and healthy aging by measuring levels of serum BDNF and resting-state fMRI data in 25 young (mean age 24.8 +/- 2.7 (SD) years) and 23 old healthy participants (mean age, 68.6 +/- 4.1 years). To identify neural hubs most essentially related to serum BDNF, we applied graph theory approaches, namely the new data-driven and parameter-free approach eigenvector centrality (EC) mapping. The analysis revealed a positive correlation between serum BDNF and EC in the premotor and motor cortex in older participants in contrast to young volunteers, where we did not detect any association. This positive relationship between serum BDNF and EC appears to be specific for older adults. Our results might indicate that the amount of physical activity and learning capacities, leading to higher BDNF levels, increases brain connectivity in (pre)motor areas in healthy aging in agreement with rodent animal studies. Pilot results have to be replicated in a larger sample including behavioral data to disentangle the cause for the relationship between BDNF levels and connectivity.

Authors: K. Mueller, K. Arelin, H. E. Moller, J. Sacher, J. Kratzsch, T. Luck, S. Riedel-Heller, A. Villringer, M. L. Schroeter

Date Published: 2nd Feb 2016

Publication Type: Not specified

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