Biology subjects

Ullrich, E.

Publications and source records attributed to Ullrich, E..

3 recordsLinked to original sources

bioRxiv2026

Menin-Inhibition Sensitizes Acute Myeloid Leukemia to CLEC12A-Directed CAR Cell Therapy

Menin inhibitors targeting the Menin-KMT2A chromatin complex have emerged as highly selective therapies for KMT2A-rearranged (KMT2A-r) and NPM1-mutated (NPM1mut) acute myeloid leukemia (AML), with recent regulatory approval and increasing interest in combination strategies. In contrast, CAR cell therapies have not yet been successfully established for AML. Here, we show that menin-inhibition primes KMT2A-r and NPM1mut AML for CAR-based targeting by inducing robust and uniform expression of the myeloid antigen CLEC12A (CLL-1). Menin inhibitors did not impair T or NK cell viability, phenotype, or effector function. We engineered second-generation CLEC12A-directed CAR T cells that efficiently eliminated CLEC12A-positive AML. Across in vitro systems and xenograft models, the combination therapy consistently outperformed either monotherapy, resulting in profound disease control and significantly prolonged survival, with evidence of near-complete leukemia eradication in vivo. These findings support epigenetic priming with menin inhibitors to enhance CLEC12A-directed CAR cell-therapy in these AML subtypes. SignificanceMenin inhibitors, now approved for AML treatment, induce the immune target CLEC12A in NPM1mut and KMT2A-r AML subtypes and sensitize AML cells to CLEC12A-directed CAR T cells without compromising immune function. As CLEC12A-CARs are already in clinical testing, this combination is immediately actionable for clinical investigation.

cancer biology↗

bioRxiv2025

Haematopoietic loss of KDM6A impairs cardiac recovery in heartfailure via epigenetic reprogramming of myeloid cells

Clonal haematopoiesis (CH) is recognized as a potent independent risk factor for cardiovascular disease (CVD). While mutations in common CH-associated genes, such as DNMT3A and TET2, have been extensively studied, the pathological roles of other CH mutations remain poorly understood. Among these is KDM6A (UTX), an X-linked histone demethylase recently found to be commonly mutated in patients with heart failure. The mechanistic implications of KDM6A mutations in cardiac dysfunction remain largely unknown. Here, using multi-omics profiling and functional characterisation of murine models and patient-derived data, we demonstrate that haematopoietic loss of KDM6A substantially impairs cardiac recovery following myocardial infarction (MI). KDM6A deficiency enhances systemic and cardiac inflammation, characterized by augmented myeloid cell infiltration into the infarcted murine heart. Single-cell chromatin accessibility and single-cell RNA sequencing analyses revealed profound epigenetic and transcriptional reprogramming in KDM6A-deficient myeloid cells, notably CCR2 recruited macrophages and neutrophils. These cells exhibited heightened inflammatory (Il1b, Nlpr3, Saa3) and chemotactic signatures (Ccr2, Mif, Cxcl12), increased activation of inflammatory transcription factor networks (AP-1, C/EBP), disrupted chromatin architecture, and enhanced glycolytic activity. Clinically, patients with heart failure harbouring KDM6A-driven CH exhibited increased pro-inflammatory monocyte signatures (CCR2, NLPR3, NFKB1, FOS, JUN, IL6R, IL32), underscoring the translational relevance. Integrative analyses further predicted pathogenic crosstalk between KDM6A-mutated monocytes and cardiac resident cells and was experimentally validated by demonstrating that KDM6A-silenced macrophages drive cardiomyocyte hypertrophy and cardiac fibroblast activation. Our findings establish a critical mechanistic link between KDM6A-driven CH, immune dysregulation, and worsened cardiac outcomes post-MI, highlighting novel avenues for personalized therapeutic strategies in heart failure.

cell biology↗

bioRxiv2025

Deciphering human heart failure with preserved ejection fraction (HFpEF) at single cell resolution

BACKGROUNDHeart failure with preserved ejection fraction (HFpEF) is a complex and growing condition, representing over half of all heart failure cases. Despite its high morbidity and mortality, its heterogeneity and limited therapeutic options pose significant challenges. Understanding the molecular mechanisms driving HFpEF is essential for the development of new therapies to improve patient outcomes. METHODSWe performed single-nucleus RNA sequencing of nuclei obtained from endomyocardial biopsies of six patients with HFpEF. The obtained dataset was integrated with a dataset of 12 healthy human hearts and their transcriptomic differences were analyzed. RESULTSAfter quality control and integration of the datasets, nine major cardiac cell types were annotated. HFpEF cardiomyocytes were characterized by a reduction in genes associated with aerobic respiration and fatty acid metabolism and showed an upregulation of RHOA/ROCK1 signaling, which was validated using immunofluorescence staining in human HFpEF myocardial sections. Endothelial cells exhibited signs of increased apoptosis, SEMA3 signaling and signs of reduced VEGFA signaling as well as a reactivation of a fetal gene signature. In line with a prominent role of cardiac fibrosis in HFpEF, we observed increased signs of fibroblast activation and proliferation, and reduced signs of IFN{gamma} signaling in HFpEF which was most pronounced in activated fibroblasts. Treatment of human cardiac fibroblast with rhIFN{gamma} resulted in decreased collagen contents. Macrophages from HFpEF myocardium showed a pro-inflammatory transcriptomic signature and showed increased expression of MHC-II molecules. This was associated with signs of an increased IFN{gamma} response. CONCLUSIONOur results provide insights into the transcriptional diversity of HFpEF recapitulating structural, functional, and molecular hallmarks of the disease and provide mechanistic insights which might represent therapeutic targets and biomarkers to improve outcome of patients with HFpEF. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIWe provide a single-nucleus RNA sequencing (snRNA-Seq) dataset from human HFpEF myocardium and demonstrate feasibility of snRNA-Seq from endomyocardial biopsies C_LIO_LIThe snRNA-Seq data confirms signs of known molecular hallmarks of HFpEF, such as metabolic changes, inflammation and fibrosis C_LIO_LIWe identify signs of regulating cellular mechanisms underlying these hallmarks, such as cytoskeleton remodeling via RhoA/ROCK1 in cardiomyocytes, and differential interferon gamma signaling in stromal and immune cells C_LI What are the clinical implications?O_LIWe provide several cell type-specific cellular mechanisms which might serve as biomarkers or therapeutic targets in the treatment of HFpEF C_LI

cell biology↗