Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.05.13.491790

Single-cell characterisation of the hematopoietic bone marrow interactome in health and disease

Ennis, S.·Conforte, A.·Cichocka, T.·Pal Dhami, S.·Nicholson, P.·Krebs, P.·O Broin, P.·Szegezdi, E.
View original source ↗Export metadata ↓

Abstract

1The bone marrow (BM) is a complex microenvironment and the primary site of hematopoiesis, coordinating the production of billions of blood cells every day. Despite the essential role of the hematopoietic niche in maintaining hemostasis and its relevance to hematopoietic diseases, many aspects of this environment remain poorly characterised due to experimental hurdles. Here we present a high-resolution characterisation of the niche in health and acute myeloid leukemia (AML) by establishing a comprehensive single-cell gene expression database of nearly 340,000 BM constituent cells encompassing all disease stages (healthy BM, AML at diagnosis, remission and relapse). We characterised the cell type composition of the BM and found that the proportions of both myeloid and lymphoid lineage cell types are significantly altered in AML. We also determined broadscale dysregulation of gene expression in almost all BM cell types upon establishment of AML, indicating that the entire niche is disrupted by the disease. Given the importance of interactions between hematopoietic cells and their microenvironment in regulating their function and properties, we determined all possible ligand-receptor interactions between hematopoietic stem and progenitor cells (HSPC) and every other BM constituent cell type. This analysis revealed a remarkable expansion of HSPC interactions in AML involving multiple BM constituent cells that can drive dysregulated HSPC-cell adhesion, immunosuppression and enhanced cytokine signalling. In particular, we found that interactions involving TGFB1 become widespread in AML and present evidence that these interactions can drive AML cell quiescence in vitro, thus highlighting TGFB1 signalling as a potential target for increasing drug sensitivity and preventing relapse. Our results shed light on potential mechanisms of enhanced competitiveness of AML HSPCs and an overall skewed microenvironment that fosters AML growth.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Ennis, S., Conforte, A., Cichocka, T., Pal Dhami, S., Nicholson, P., Krebs, P., O Broin, P., Szegezdi, E.. 2022-05-13. Single-cell characterisation of the hematopoietic bone marrow interactome in health and disease. https://doi.org/10.1101/2022.05.13.491790

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Psychoneuroimmunology of Viral Hepatitis and Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma (HCC) and viral hepatitis (VH) are recognized primarily as hepatic diseases, yet they impose a substantial neuropsychiatric disorders (NPDs) encompassing depression, anxiety, cognitive impairment, and fatigue. Whether these manifestations reflect psychological reactions or biologically grounded psychoneuroimmune dysfunction remains poorly understood. Here, we present a pre-registered systematic review and meta-analysis (PROSPERO 2026 CRD420251081757) synthesizing evidence from 24 studies combining psychosocial outcomes with immune dysregulation markers across HCC and VH populations. Bibliometric and network analyses identified a growing psychoneuroimmunology research hub linking cytokine signaling, microglial activation, blood-brain barrier (BBB) disruption, and gut-liver-brain axis dysregulation to the neuropsychiatric phenotype of these diseases. Meta-analysis revealed a pooled hazard ratio (HR) of 1.92 (95% CI: 1.09-3.39) for adverse outcomes in HCC and a pooled HR of 2.28 (95% CI: 1.48-3.52) for depression associated to genetic variants in VH. TNF-a, but not IL-6, showed a tendency toward lower levels in VH patients with versus without NPDs, suggesting differential inflammatory roles. The literature, however, remains fragmented by heterogeneous designs and a paucity of longitudinal data. A psychoneuroimmunological approach, integrating immune, endocrine, neural, and psychosocial dimensions, is essential for capturing the full systemic impact of HCC and VH and should inform future mechanistic research and multidisciplinary clinical strategies.

cancer biology↗
bioRxiv2026

Nutrient Availability as a Driver of Transcriptome Reprogramming in Osteosarcoma

Background: Gene expression in mammalian cells is intricately regulated by environmental and metabolic cues. Among these, nutrient availability represents a key feature of the tumor microenvironment and has recently emerged as a potent modulator of oncogenic signaling networks. In this study, we employed a cell-line model of osteosarcoma, a rare but highly aggressive bone malignancy affecting both humans and dogs. We demonstrate that altering the concentration of a single nutrient can profoundly reprogram gene expression in osteosarcoma cells, revealing a previously underexplored phenomenon: nutrient-dependent gene regulation. This finding highlights potential opportunities for therapeutic intervention and underscores the broader implications of metabolic regulation for personalized medicine and nutrition. Methods/Results: We performed bulk RNA sequencing of an established osteosarcoma cell line cultured under varying concentrations of two key nutrients, glucose and glutamine. Differential gene expression analysis revealed a pronounced nutrient-dependent transcriptional response. The identified genes were functionally associated with pathways involved in cancer, development, nervous system regulation, metabolism, cellular signaling, and immune responses. We identified seven distinct expression patterns, one of which exhibited a striking correlation with cell growth rate and resembled a FOS-like transcriptional signature. Notably, the proto-oncogene FOS was among the identified genes and displayed a strong growth-rate-dependent expression pattern. Conclusion/Impact: Our findings demonstrate that modulation of nutrient availability profoundly reshapes the gene expression landscape of osteosarcoma cells, revealing nutrient-responsive targets with potential therapeutic relevance. This work expands our understanding of metabolic regulation in cancer and suggests that nutrient-based interventions may provide a controllable means of influencing tumor progression. Beyond oncology, such approaches may also have broader implications for developmental biology, autoimmune disorders, and nervous system function. More broadly, this study highlights the potential of metabolic interventions as a strategy for targeted modulation of gene expression programs.

cancer biology↗
bioRxiv2026

Synthetic chromatin engineering for STAT1 reactivation toward restoring cisplatin sensitivity in breast cancer

Chemoresistant cancers acquire transcriptomic and epigenetic alterations through changes in transcription factor activity and chromatin accessibility. Integrative in silico analyses identified STAT1 as a recurrently suppressed transcription factor in cisplatin-resistant breast cancer. Using cisplatin-resistant triple-negative breast cancer (TNBC) MDA-MB-231 cells, we further confirmed reduced STAT1 expression and activity, accompanied by defective nuclear translocation, indicating that suppression of STAT1 signaling contributes to cisplatin resistance in breast cancer. To restore STAT1 activity, we sought to promote its nuclear localization and transcriptional activation through chromatin engineering. Based on the identification of PHF6 as a direct STAT1-binding protein through in silico and in vitro analyses, we engineered Dual Reader 3 (DR3), a PHF6-derived synthetic chromatin regulator designed to enhance both STAT1 interaction and chromatin engagement through histone H2B ubiquitination. DR3 induced STAT1-associated transcriptional programs, including inflammatory and tumor-suppressive miRNAs. Mechanistically, DR3 physically promoted STAT1 nuclear translocation, activated STAT1 through a non-canonical S727-dependent mechanism independent of Tyr701 phosphorylation, and enhanced chromatin accessibility at STAT1-responsive regulatory regions through histone H2B ubiquitination. CUT&RUN analysis further revealed coordinated transcriptional and epigenetic remodeling associated with DR3-mediated STAT1 activation, including upregulation of HIPK2, which enhanced cellular sensitivity to cisplatin by strengthening the intrinsic DNA damage response. Finally, we investigated whether STAT1 reactivation could alleviate acquired cisplatin resistance. In vivo delivery of DR3 restored cisplatin sensitivity in resistant breast tumors. By coupling STAT1 nuclear translocation with chromatin remodeling, DR3 reactivated STAT1-dependent transcriptional programs and restored cisplatin sensitivity in breast cancer. Together, this study establishes transcription factor reactivation through synthetic chromatin engineering as a potential therapeutic strategy for overcoming chemoresistance in solid tumors.

cancer biology↗