A5069339719- Acute Myeloid Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Epigenetics and DNA Methylation
- Mesenchymal stem cell research
- Multiple Myeloma Research and Treatments
- Immune cells in cancer
- Hematopoietic Stem Cell Transplantation
- Bone and Joint Diseases
- Protein Degradation and Inhibitors
- Genomics and Chromatin Dynamics
- Platelet Disorders and Treatments
- Chronic Lymphocytic Leukemia Research
- RNA Research and Splicing
- Chronic Myeloid Leukemia Treatments
- Kruppel-like factors research
- Genetic Syndromes and Imprinting
- Genomic variations and chromosomal abnormalities
- Hematological disorders and diagnostics
- Immunodeficiency and Autoimmune Disorders
- Hemoglobinopathies and Related Disorders
- Blood disorders and treatments
- Biosensors and Analytical Detection
- Cell Image Analysis Techniques
Heidelberg University
2016-2025
University Hospital Heidelberg
2016-2025
University Medical Centre Mannheim
2016-2025
Dana-Farber Cancer Institute
2022-2024
Broad Institute
2023-2024
University of Mannheim
2022-2023
Abstract Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack strategies for the purification newly identified cell types impede their functional characterization large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps human blood bone marrow that quantitatively link expression up to 197 surface markers identities biological processes across all main hematopoietic in...
Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization these remains elusive with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic (LSCs) underlie mortality but are difficult isolate due their low abundance high similarity healthy hematopoietic (HSCs). Here, we demonstrate that LSCs, HSCs, pre-leukemic can be identified molecularly profiled by combining single-cell transcriptomics...
The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors increasing age, discovered the heterogeneous mSV landscapes hematopoietic stem progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones our cohort confined to individuals >60. Cells already harboring more likely acquire additional somatic variants, including...
Abstract Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods directly characterize functional consequences. We present computational method, scNOVA, which uses Strand-seq perform haplotype-aware integration SV discovery and molecular phenotyping single cells by using nucleosome occupancy infer gene expression as readout. Application leukemias cell lines identifies local effects copy-balanced rearrangements...
Somatic mutations in genes coding for splicing factors, e.g. SF3B1, U2AF1, SRSF2, and others are found approximately 50% of patients with Myelodysplastic Syndromes (MDS). These have been predicted to frequently occur early the mutational hierarchy disease therefore making them particularly attractive potential therapeutic targets. Recent studies cell lines engineered carry factor revealed a strong association elevated levels DNA:RNA intermediates (R-loops) dependency on proper ATR function....
Abstract The bone marrow (BM) stroma in myeloid neoplasms is altered and it hypothesized that this cell compartment may also harbor clonal somatically acquired mutations. By exome sequencing of vitro expanded mesenchymal stromal cells (MSCs) from n = 98 patients with myelodysplastic syndrome (MDS) 28 healthy controls we show these accumulate recurrent mutations genes such as ZFX (n 8/98), RANK 5/98), others. MDS derived MSCs display higher mutational burdens, increased replicative stress,...
Abstract Mutations in the cohesin complex components ( STAG2, RAD21, SMC1A, SMC3 , and PDS5B) are recurrent genetic drivers myelodysplastic neoplasm (MDS) acute myeloid leukemia (AML). Whether different subunit mutations share clinical characteristics prognostic significance is not known. We analyzed 790 cohesin-mutant patients from Dana-Farber Cancer Institute (DFCI) Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, identified subunit-specific clinical, prognostic,...
Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement this treatment indication. Here, by combining 5-azacytidine (5-AZA) the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration erythroid differentiation hematopoietic stem progenitor cells (HSPCs) MN patients 20/31 cases (65%) versus 9/31 (29%) treated 5-AZA alone. This effect requires direct contact HSPCs bone marrow...
Abstract Background Robust and reliable in vitro vivo models of primary cells are necessary to study the pathomechanisms Myelodysplastic Neoplasms (MDS) identify novel therapeutic strategies. MDS-derived hematopoietic stem progenitor (HSPCs) reliant on support bone marrow (BM) derived mesenchymal stroma (MSCs). Therefore, isolation expansion MCSs essential for successfully modeling this disease. For clinical use healthy MSCs isolated from human BM, umbilical cord blood or adipose tissue,...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most frequent cause of death from cancer. Circulating tumor cells (CTCs) with stem-like characteristics lead to distant metastases and thus contribute dismal prognosis PDAC. Our purpose investigate role stemness in CTCs derived a genetically engineered mouse model PDAC further explore potential molecular mechanisms. The publically available RNA sequencing dataset GSE51372 was analyzed, (CTC-S) or without (CTC-N) features were...
In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement clinical phase I trial for MDS patients (NCT01736436; 2012-11-26). the current study we aimed...
Myelodysplastic Neoplasms (MDS) are hypothesized to re-model their bone marrow (BM) microenvironment reinforce conditions for propagation. In this study, we investigated interactions between MDS cells and the BM niche at single cell level. a patient-derived xenograft (PDX) model, analyzed 13,000 of different murine populations after long-term (>24 weeks) exposure versus healthy human grafts. Subsequently, over 24,000 primary enriched non-hematopoietic compartment by using whole fragments...
ABSTRACT Single-cell genomics has transformed our understanding of complex cellular systems. However, excessive costs and a lack strategies for the purification newly identified cell types impede their functional characterization large-scale profiling. Here, we have generated high content single-cell proteo-genomic reference maps human blood bone marrow that quantitatively link expression up to 197 surface markers identities biological processes across all major hematopoietic in healthy...
Abstract Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack feasible disease models. Previously, we have established robust patient-derived xenograft (PDX) model for MDS. Here demonstrate the first time that this applicable as preclinical platform to address pending clinical questions interrogating efficacy and safety thrombopoietin receptor agonist eltrombopag. Our study included n = 49 xenografts generated from 9 MDS patient samples. Substance was evidenced...
Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMA) are promising therapeutic approaches acute myeloid leukemia (AML) high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor indirect transcriptional repressor the factor MCL-1, has previously shown clinical activity AML. Availability biomarkers for response to alvocidib + 5-azacytidine (5-AZA) could also extend rationale this treatment...
Although acute promyelocytic leukemia (APL) has evolved to the AML entity with best prognosis, typical 'early death' (ED) events still account for mortality rates of ∼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis n = 7 APL ED cases compared long term remission. We discovered proteins S100A8/S100A9 and EFEMP1 as most differentially expressed factors. In an independent cohort 58 patients over-expression was associated a...
Abstract Somatic structural variants (SVs) are widespread in cancer genomes, however, their impact on tumorigenesis and intra-tumour heterogeneity is incompletely understood, since methods to functionally characterize the broad spectrum of SVs arising cancerous single-cells lacking. We present a computational method, scNOVA, that couples SV discovery with nucleosome occupancy analysis by haplotype-resolved single-cell sequencing, systematically uncover effects cis -regulatory elements gene...