Biology subjects

Stilgenbauer, S.

Publications and source records attributed to Stilgenbauer, S..

9 recordsLinked to original sources

bioRxiv2026

Fendioxypyracil Exhibits Potent Inhibition of PPO-Resistant Mutant Enzymes and Robust Activity Against PPO-Resistant Amaranthus

Background: Resistance to protoporphyrinogen oxidase (PPO) inhibiting herbicides is mainly driven by diverse target-site mutations, reducing the effectiveness of this site of action in row crop systems. Fendioxypyracil is a newly developed PPO inhibitor with high intrinsic grass and broadleaf activity, but its performance against resistant populations and target-site enzyme variants remains insufficiently characterized. Results: Enzyme assays using PPO2 from Amaranthus palmeri and Setaria viridis demonstrated that fendioxypyracil maintained low IC50 values across a broad range of resistance associated mutations, including dG210 deletion and G210, R128, and G399 substitutions, whereas oxadiazon, tiafenacil, and saflufenacil showed substantial loss of potency. Greenhouse dose response experiments confirmed strong fendioxypyracil efficacy, with susceptible and G399A populations controlled at <3 g ai/ha, while dG210 and R128G populations showed only moderate shifts in sensitivity but remained effectively controlled at the recommended rate. Transgenic Arabidopsis thaliana expressing resistant PPX2 alleles exhibited faster and more severe injury with fendioxypyracil compared to saflufenacil. Field trials conducted in a PPO resistant Amaranthus palmeri population demonstrated that fendioxypyracil provided consistent weed control and density reduction, matching the performance of trifludimoxazin and saflufenacil while exceeding that of fomesafen. Conclusion: Fendioxypyracil provides robust and broad-spectrum activity against PPO resistant Amaranthus populations and target mutant enzymes, maintaining efficacy across diverse mutation backgrounds. These results demonstrate its potential as an effective tool for managing PPO inhibitor resistance and sustaining weed control in row-crop production systems.

molecular biology↗

bioRxiv2025

GPR15LG binds CXCR4 and synergistically modulates CXCL12-induced cell signaling and migration

GPR15LG, a chemokine-like ligand for the G-protein coupled receptor 15 (GPR15), is abundantly expressed in the gastrointestinal mucosa and inflamed skin. Emerging evidence suggests its involvement in inflammatory disorders and cancers. This study investigates the effects of GPR15LG on the signaling and downstream functions of C-X-C chemokine receptor type 4 (CXCR4), which plays a critical role in immune cell trafficking and cancer metastasis. The results demonstrate that GPR15LG binds to the orthosteric site of CXCR4, modulating downstream signaling in a context-dependent manner. Specifically, GPR15LG enhances CXCL12-mediated CXCR4 signaling synergistically, promoting wound healing and cell migration across various cell types, including CD4+ T cells and cancer cells. These findings underscore the role of GPR15LG in inflammation and metastasis, offering potential therapeutic avenues for CXCR4-mediated diseases. TeaserGPR15LG binds CXCR4 thereby modulating CXCL12/CXCR4 signaling and immune and cancer cell trafficking.

cell biology↗

bioRxiv2022

Nucleosome repositioning in chronic lymphocytic leukaemia

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we performed a systematic comparison of high-resolution nucleosome maps in peripheral-blood B-cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of both nucleosome positioning and packing in CLL. Globally, the spacing between nucleosomes (the nucleosome repeat length, NRL) was shortened in CLL. This effect was stronger in the more aggressive IGHV-unmutated than IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites were linked to active chromatin remodelling and reduced DNA methylation. Nucleosomes lost or gained in CLL in comparison with non-malignant B-cells marked differential binding of 3D chromatin organisers such as CTCF as well as immune response-related transcription factors, allowing delineating epigenetic mechanisms affected in CLL. Furthermore, patients could be better assigned to CLL subtypes according to nucleosome occupancy at cancer-specific sites than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome positioning changes detected in our study, like the reduced NRL, can be exploited for liquid biopsy applications based on cell-free DNA to monitor disease progression.

genomics↗

bioRxiv2022

Chronic lymphocytic leukemia includes a tumor subset resembling memory B cells that develop early and persist

Intratumor heterogeneity (ITH) refers to the coexistence of distinct cancer cell subpopulations within a single tumor, each with unique molecular and functional properties. Understanding the dynamics and evolution of ITH is crucial for predicting tumor progression and the development of therapy resistance. Here, we conducted a comprehensive investigation of ITH in Chronic Lymphocytic Leukemia (CLL) and identified a subpopulation that carried the CLL B-cell receptor rearrangement but contrasted from the CLL main population by low CD5 and high CD20 expression and highly mutated Ig-genes. This CLL-related memory B-cell population shared somatic driver mutations with the main CLL population but also exhibited exclusive somatic mutations. Phylogenetic analysis suggested a pathogenically early generation of these CLL-related B cells before monoclonal B lymphocytosis or CLL manifestation. Our data indicated that CLL-related B cells have self-replenishing potential, as they diminish upon treatment but recover indistinguishably on relapse. This contrasts with the main CLL population, which mostly represents a selective and novel expansion of the CLL-related B cells. This differentiation capacity into conventional CLL cells, and the expression of leukemic stem cell signatures further supported their tumorigenic capacity. We propose that these CLL-related B cells represent a pool of highly diversified, early-stage CLL precursor cells, which persist in the shape of "malignant memory B cells". Longitudinal analyses of these CLL precursor cells suggested that they form a reservoir of malignant, leukemia-originating cells which contribute during disease progression to CLL outgrowth and clonal evolution.

immunology↗

bioRxiv2022

Proteogenomics refines the molecular classification of chronic lymphocytic leukemia

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling. Single sentence summaryWe performed the largest proteogenomic analysis of CLL, linked proteomic profiles to clinical outcomes, and discovered a new poor outcome subgroup (ASB-CLL).

cancer biology↗

bioRxiv2021

NOTCH1 drives immune-escape mechanisms in B cell malignancies

NOTCH1 is a recurrently mutated gene in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Functional studies to investigate its role have been hampered by the inability to genetically manipulate primary human lymphoma cells, attributed to low transduction-efficacy and procedure-associated toxicity. To overcome these limitations, we have developed a novel method to retrovirally transfer genes into malignant human B cells. We generated isogenic human tumor cells from patients with CLL and MCL, differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-{gamma} signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+ T cells in vivo, further contributing to the poor clinical outcome of NOTCH1-mutated CLL and MCL.

cancer biology↗

bioRxiv2020

EOMES and IL-10 regulate anti-tumor activity of PD-1+ CD4+ T-cells in B-cell Non-Hodgkin lymphoma

The transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4+ T-cells, which has been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4+ T-cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. This was in line with an observed expansion of EOMES-positive CD4+ T-cells in leukemic E{micro}-TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription of IL-10, but rather controls a unique differentiation program in CD4+ T-cells. Moreover, EOMES was necessary for the accumulation of a specific CD4+ T-cell subset that expresses IFN{gamma} and IL-10, as well as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenic Rag2-/- mice showed that EOMES-deficient CD4+ T-cells were inferior in controlling TCL1 leukemia development compared to wildtype T-cells, even though expansion of Eomes-/- CD4+ T-cells was observed. We further showed that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, as Il10rb-deficient CD4+ T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-1+ CD4+ T-cells contribute to CLL control in an EOMES- and IL-10R-dependent manner.

cancer biology↗

bioRxiv2020

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

BackgroundIn cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground-state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations. MethodsWe developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation. ResultsMethyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level. ConclusionsMethyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies.

cancer biology↗

bioRxiv2018

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Oncogenic MYC activation promotes cellular proliferation in Burkitt lymphoma (BL), but also induces cell cycle arrest and apoptosis mediated by TP53, a tumor suppressor gene that is mutated in 40% of BL cases. To identify therapeutic targets in BL, we investigated molecular dependencies in BL cell lines using RNAi-based, loss-of-function screening. By integrating genotypic and RNAi data, we identified a number of genotype-specific dependencies including the dependence of TCF3/ID3 mutant cell lines on TCF3 and of MYD88 mutant cell lines on TLR signaling. TP53 wild-type (TP53wt) BL were dependent on MDM4, a negative regulator of TP53. In BL cell lines, MDM4 knockdown induced cell cycle arrest and decreased tumor growth in a xenograft model in a p53-dependent manner, while small molecule inhibition of the MDM4-p53 interaction restored p53 activity resulting in cell cycle arrest. Consistent with the pathogenic effect of MDM4 upregulation in BL, we found that TP53wt BL samples were enriched for gain of chromosome 1q which includes the MDM4 locus. 1q gain was also enriched across non-BL cancer cell lines (n=789) without TP53 mutation (23% in TP53wt and 12% in TP53mut, p<0.001). In a set of 216 cell lines representing 19 cancer entities from the Achilles project, MDM4 was the strongest genetic dependency in TP53wt cell lines (p<0.001).\n\nOur findings show that in TP53wt BL, MDM4-mediated inhibition of p53 is a mechanism to evade cell cycle arrest. The data highlight the critical role of p53 as a tumor suppressor in BL, and identifies MDM4 as a key functional target of 1q gain in a wide range of cancers, which is therapeutically targetable.

cancer biology↗