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February 2018 - September 2021
August 2004 - March 2008
April 2008 - June 2018
Publications
Publications (207)
This review aims to provide an overview of the latest developments in the classification and molecular understanding of aggressive B‐cell lymphomas, specifically focusing on diffuse large B‐cell lymphoma (DLBCL) and high‐grade B‐cell lymphoma (HGBL). Advances in molecular techniques have led to novel ways to classify these lymphomas based on clinic...
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and has increased incidence in the elderly. Approximately 40% of pts with DLBCL are >70 yrs old. In older/frail pts with untreated DLBCL, the attenuated chemotherapy regimen R-miniCHOP is the standard of care with a 2-yr overall survival (OS) of approximately 60%...
Management of relapsed/refractory Large B Cell Lymphoma (r/r LCBL) after CD19 Chimeric Antigen Receptor (CAR) T cells represents a major clinical challenge. Glofitamab and Epcoritamab, two CD3xCD20 bispecific T cell-recruiting antibodies, have recently been approved for third-line treatment. However, real-world experience with these bispecifics is...
Introduction: Central nervous system lymphomas (CNSL) are aggressive extranodal Non-Hodgkin lymphomas confined to the CNS compartment, mostly classified as diffuse large B-cell lymphomas. The gold standard for CNSL diagnosis is histopathological assessment of tumor tissue obtained by stereotactic brain biopsies. Yet, in high-risk situations or when...
Roughly 2/3 of patients with large B-cell lymphoma (LBCL) are cured using R-CHOP-like immunochemotherapies, CAR-T-cell therapies or T-cell-engaging bispecific antibodies. The remaining patients experience relapsed or refractory disease (r/r LBCL), with limited treatment options and a dismal prognosis. Molecular insights into the disease hold the pr...
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma derived from transformed dark zone germinal center B cells. Intensive polychemotherapy in combination with the CD20-directed monoclonal antibody (mAb) rituximab is used as first-line therapy with high cure rates. The prognosis of patients significantly decreases in elderly and unfit patients or...
Introduction
Patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) after CD19 chimeric antigen receptor (CAR)-T cell therapy are challenging to treat. CD20xCD3 T-cell-engaging bispecific antibodies (BsAbs) have emerged as a promising therapeutic option for these pts. In the pivotal trials, glofitamab and epcoritamab demonstr...
Various clinical scenarios preclude or delay invasive stereotactic biopsies and subsequent histopathological assessment for the diagnosis of central nervous system lymphoma (CNSL), necessitating innovative minimal-invasive strategies. We designed a digital droplet PCR (ddPCR) assay for minimal-invasive identification of CNSL in clinical practice by...
Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation sign...
Identifying genotype-guided drug combinations in cancer therapy represents an unmet medical need and is important in enhancing efficacy and reducing toxicity. However, the exponential increase in combinatorial possibilities constrains the ability to identify and validate effective drug combinations. In this context, we have developed Onko_DrugCombS...
Mature T-cell lymphomas and leukemias (mTCL) comprise a clinically and genetically heterogeneous group of lymphoid malignancies. Most subtypes of peripheral T-cell lymphomas and leukemic T-cell malignancies show an aggressive clinical course and poor prognosis. Thus, these diseases urgently require novel therapeutic strategies. Taking advantage of...
The diagnosis and treatment of malignant lymphoma is rapidly advancing, offering hope but also highlighting inherent limitations. Technological breakthroughs in sequencing technologies enable more precise subtyping and risk stratification. For example, in diffuse large B-cell lymphoma (DLBCL), exome sequencing revealed molecular subtypes. Understan...
Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated...
The structure and dynamics of F‐actin networks in the cortical area of B cells control the signal efficiency of B‐cell antigen receptors (BCRs). Although antigen‐induced signaling has been studied extensively, the role of cortical F‐actin in antigen‐independent tonic BCR signaling is less well understood. Because these signals are essential for the...
In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the P...
Background
Publication of the L-MIND-study led to the approval of tafasitamab/lenalidomide (TL) for patients with relapsed oder refractory diffuse large B-cell lymphoma (r/r DLBCL), who were ineligible for autologous stem-cell transplantation (ASCT). The findings of the L-MIND-study showed an overall response rate (ORR) of 60%, complete response ra...
Background. Diffuse large B-cell lymphoma is the most common aggressive B-cell lymphoma mainly affecting elderly patients. The treatment goal is usually cure, however, older and frail patients typically exhibit a growing number of comorbidities that significantly increase treatment-related morbidity and mortality thus limiting the treatment goal du...
The PIM kinase family consists of 3 proto-oncogenic proteins: PIM1, PIM2 and PIM3, expressed in numerous malignancies, including DLBCL. PIM kinases regulate crucial processes, such as proliferation, apoptosis, metabolism, or migration, therefore their inhibition is of great interest as a potential therapeutic strategy. Although recent studies have...
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and its incidence increases with age. Approximately 40% of patients with DLBCL are older than 70 years. Since the addition of the anti-CD20 antibody rituximab to CHOP regime (cyclophosphamide, doxorubicin, vincristine, and prednisone) prognosis in elderly patients...
Burkitt lymphoma cells (BL) exploit antigen-independent tonic signals transduced by the B cell antigen receptor (BCR) for their survival, but the molecular details of the rewired BLspecific BCR signal network remain unclear. A loss of function screen revealed the SH2 domain-containing 5`-inositol phosphatase 2 (SHIP2) as a potential modulator of BL...
Secondary central nervous system lymphoma (SCNSL) is a rare and difficult to treat type of Non-Hodgkin lymphoma characterized by systemic and central nervous system (CNS) disease manifestations. In this study, 124 patients with SCNSL intensively treated and with clinical long-term follow-up were included. Initial histopathology, as divided in low-g...
Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease comprised of at least 5 recognized molecular subtypes. Cluster 5/ MCD tumors frequently exhibit concurrent alterations of the Toll-like receptor (TLR) and B-cell receptor (BCR) pathway members, MYD88L265P and CD79B, and have a less favorable prognosis. In no...
Although T-cell-engaging therapies are highly effective in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL), responses are often not durable. To identify tumor-intrinsic drivers of resistance, we quantified in-vitro response to CD19-directed chimeric antigen receptor T-cells (CD19-CAR) and bispecific antibodies (BsAb) ac...
Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response asses...
Background
Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.
Patients and methods
To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we performed a comprehensive...
Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell–specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-...
Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, mere BCR signaling without subsequent co-stimulation by T cells commits B cells to death rather than to differentiation into immune effector cells. It remains mysterious how the BCR simultaneously executes the opposing roles of B cell priming necessary for proper imm...
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance b...
In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 iming to highlight achievements in the diagnostics and treatment of blood disorders and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology...
Genetic alterations in the DNA Damage Response (DDR) pathway are a frequent mechanism of resistance to CIT in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumour cells and macrophages. Here, we show that loss of multiple different members of the DDR pathway...
Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood.
We performed a comprehensive genome-wide analysis o...
Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative pro...
SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconj...
Personalized medicine aims to tailor treatment to patients based on their individual genetic or molecular background. Especially in diseases with a large molecular heterogeneity, such as diffuse large B-cell lymphoma (DLBCL), personalized medicine has the potential to improve outcome and/or to reduce resistance towards treatment. However, integrati...
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Both biologically and clinically, DLBCL represents a highly heterogeneous disease. DLBCL has been subdivided into germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCL, on the basis of gene expression profiling, which separates DLBCL according...
Large-scale genomic profiling of pancreatic cancer (PDAC) has revealed two distinct subtypes: ‘classical’ and ‘basal-like’. Their variable coexistence within the stromal immune microenvironment is linked to differential prognosis; however, the extent to which these neoplastic subtypes shape the stromal immune landscape and impact clinical outcome r...
The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the dev...
Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and...
Significance
Fifty percent of diffuse large B cell lymphoma (DLBCL) evade immune-surveillance via somatic genetic lesions abrogating the expression of the class I major histocompatibility complex (MHC-I) complex on the cell surface, thus preventing the presentation of tumor neoantigens to the immune system. The results herein significantly extend t...
Aggressive large B‐cell lymphomas (LBCLs) represent a frequent but clinically and molecularly heterogeneous group of tumors. Technological advances over the last decades prompted the development of different classification schemas to either sharpen diagnoses, dissect molecular heterogeneity, predict outcome, or identify rational treatment targets....
Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and ar...
R-CHOP immunochemotherapy remains standard frontline therapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. However, this therapy is ineffective in approximately 1/3 of patients, underscoring the need for better treatment modalities. Targeting DLBCL oncogenic drivers is a promising strategy to improve the treatment efficacy and...
Key PointsSequencing-based approaches are readily used for molecular classifications of diffuse large B-cell lymphomaGenetically distinct diffuse large B-cell lymphoma provides insights into unique lymphomagenesis, prognosis prediction, and combination of targeted treatmentsGenetic classifiers identify novel vulnerabilities and inform clinical tria...
Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome of the majority of BL patients, chemotherapy-related toxicity and disease relapse remain as major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 sc...
T-cell/histiocyte-rich large B cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quan...
Many prior studies have focused on the role of mutations in epigenetic factors in cancer (e.g., EZH2, CREBBP, EP300, KMT2C, KMT2D) but drugs targeting these mutations have shown only modest activity in patients. Here we identify overexpression of KDM4A and KDM4C, two erasers of histone H3K9 methylation in multiple cancers, and demonstrate that thei...
Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles – such as cellular senescence – remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of b...
Serum albumin a well‐known risk factor predicting outcome in many solid tumors. We explore the role of low serum albumin (≤3.5 g/dL) as an independent risk factor in elderly patients with aggressive B‐cell lymphoma. Outcome of 429 patients treated with R‐CHOP‐14 in the RICOVER‐60 trial and available serum albumin were analyzed in this retrospective...
Tumour heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is known to affect the efficacy of cancer therapy, most personalized treatment approaches do not account for intratumour heterogeneity. We addressed this issue by studying the heterogeneity of nodal B-cell lymphomas...
Large B-cell lymphomas (LBCLs) represent a frequent but clinically and morphologically heterogeneous group of tumors. Technological advances over the last 2 decades prompted the development of new classification schemas to sharpen diagnoses, dissect molecular heterogeneity, and identify rational treatment targets. Despite increased molecular unders...
Tightly regulated activity of the transcription factor MYC is essential for orderly cell proliferation. Upon deregulation, MYC elicits and promotes cancer progression. Proteasomal degradation is an essential element of MYC regulation, initiated by phosphorylation at Serine62 (Ser62) of the MB1 region. Here, we found that Ser62 phosphorylation peaks...
Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting...
Tumor heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is well-known to affect the efficacy of anti-cancer drugs, most personalized treatment approaches do not account for intratumor heterogeneity. We addressed this issue by studying the heterogeneity of lymph node-derive...
Key Points
Analyses of recurrent mutations, copy number alterations, and structural variants reveal complementary immune evasion mechanisms in cHL. The mutational burden in EBV– cHLs is among the highest reported, potentially contributing to the efficacy of PD-1 blockade.
The emergence of large-scale multi-omics data warrants method development for data integration. Genomic studies from cancer patients have identified epigenetic and genetic regulators – such as methylation marks, somatic mutations, and somatic copy number alterations (SCNAs), among others – as predictive features of cancer outcome. However, identifi...
Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBL) are aggressive tumors with distinct cells of origin and pathomorphological features. However, these lymphomas share certain transcriptional signatures and aberrant signaling pathways. CHLs and PMBLs both exhibit constitutive activation of NF-κB and JAK/STAT signal...
Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease with recognized transcriptional subtypes associated with normal cells of origin, activated B-cell (ABC) and germinal center B-cell (GCB) tumors. Emerging data suggested that additional heterogeneity existed, prompting us to comprehensively characterize genom...
Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death...
Transforming growth factor‑β1 (TGF-β1) is a versatile cytokine. It has context-dependent pro- and anti-cell proliferation functions. Activation of latent TGF-β1 requires release of the growth factor from pro-complexes and is regulated through TGF-β binding proteins. Two types of TGF-β binding partners, latent TGF-β-binding proteins (LTBPs) and leuc...
B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-ag...
Background
Non-Hodgkin lymphomas are clinically and molecularly heterogeneous diseases. In addition to clinical symptoms, morphology and immunophenotype, molecular diagnostics are increasingly used to more accurately classify lymphomas into homogeneous, clinically relevant and non-overlapping entities.
Conclusion
Molecular classifiers are used to...
The emergence of large-scale multi-omics data warrants method development for data integration. Genomic studies from cancer patients have identified epigenetic and genetic regulators – such as methylation marks, somatic mutations, and somatic copy number alterations (SCNAs), among others – as predictive features of cancer outcome. However, identifi...