Biology subjects

Russell, L. J.

Publications and source records attributed to Russell, L. J..

6 recordsLinked to original sources

bioRxiv2026

PRINCIPLES GOVERNING ENDOTHELIAL CAVEOLAE ORGANIZATION DURING ANGIOGENESIS

Caveolae, flask-shaped membrane invaginations highly enriched in endothelial cells, play a central role in buffering membrane tension, yet the principles governing their spatial organization remain elusive. This investigation sought to generate the most comprehensive and systematic analysis of blood vessel caveolar spatial organization. To do so, our group leveraged micropatterning technologies to impose precise biophysical constraints on endothelial cell geometry to probe how caveolae are organized under defined tensional and polarity environments. These experiments were integrated with a high-throughput spatial cell mapping computational pipeline for analyzing thousands of caveolae, providing an extremely high-fidelity analysis. Our results provide a governing framework of how total cellular caveolae are spatially organized during random and directional migration, non-motile polarized, nascent and stable monolayers with differing confinement levels as well as in angiogenic vasculature in vivo. Broadly, our results demonstrated caveolae preferentially organized in the rear of migrating and polarized endothelial cells. In differing monolayer configurations, caveolae default to a peri-junctional spatial organization. Lastly, in mouse retinal blood vessels caveolae are most prominent in the vascular front due to their responsiveness to vascular endothelial growth factor signaling. Overall, these results strongly suggest that caveolae cellular arrangement and number are highly predictive of vascular stability and remodeling states.

cell biology↗

bioRxiv2025

B-cell precursor acute lymphoblastic leukaemia with IGH::CEBP rearrangement: what have we learnt over the years?

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is a haematologic malignancy marked by the rapid proliferation of immature B cells in the bone marrow. While BCP-ALL most commonly affects children aged 1-5 years, it remains the most prevalent subtype of ALL in adolescence and adulthood. Chromosomal translocations involving the immunoglobulin (IG) locus and partner genes are proven useful for risk stratification and guiding clinical trials for therapeutic decision. This includes translocations with CCAAT/enhancer-binding proteins (CEBP), which are particularly rare. This rarity has limited efforts to characterise their genetic and clinical profiles, making risk stratification for IGH::CEBP-rearranged BCP-ALL challenging. In this letter, we review the clinical and demographic characteristics of all reported IGH::CEBP cases prior to 2024 and introduce new cases, with preliminary analysis to encourage further investigation into this poorly understood subtype. This study delivers new insights into the molecular and cytogenetic landscape of IGH::CEBP rearrangements in BCP-ALL, and lays a foundation for further investigation into CEBP family roles in haematopoietic development and leukemogenesis, especially in the context of Down syndrome. Finally, it introduces the ongoing international collaborative effort to assemble the largest known IGH::CEBP cohort for comprehensive risk stratification and prognostic evaluation.

cancer biology↗

bioRxiv2023

The discovery of an evolutionarily conserved enhancer within the MYEOV locus suggests an unexpected role for this non-coding region in cancer

The myeloma overexpressed gene (MYEOV) has been proposed to be a proto-oncogene due to high RNA transcript levels found in multiple cancers, including myeloma, breast, lung, pancreas and esophageal cancer. The presence of an open reading frame (ORF) in humans and other primates suggests protein-coding potential. Yet, we still lack evidence of a functional MYEOV protein. It remains undetermined how MYEOV overexpression affects cancerous tissues. In this work, we show that MYEOV has originated and may still function as an enhancer, possibly regulating CCND1. Firstly, MYEOV 3 end enhancer activity was confirmed in humans using publicly available ATAC-STARR-seq data, performed on B-cell-derived GM12878 cells. We detected enhancer histone marks H3K4me1 and H3K27ac overlapping MYEOV in multiple healthy human tissues, which include B cells, liver and lung tissue. The analysis of 3D genome datasets revealed chromatin interactions between the MYEOV-3-enhancer and the proto-oncogene CCND1. BLAST searches and multi-sequence alignments results showed that this human enhancer element is conserved from the amphibians/amniotes divergence, with a 273 bp conserved region also found in all mammals, and even in chickens, and it consistently located near the corresponding CCND1 orthologues. Furthermore, we observed conservation of active enhancer state in the MYEOV orthologues of four non-human primates, dog, rat and mouse. When studying this homologous region in mice, where the ORF of MYEOV is absent, we not only observed an enhancer chromatin state but also found interactions between the mouse enhancer homolog and Ccnd1 using 3D-genome interaction data. This is similar to the interaction observed in humans and, interestingly, coincides with CTCF binding sites in both species. Taken together, this suggests that MYEOV is a primate-specific gene with a de novo ORF that originated at an evolutionarily older enhancer region. This deeply conserved enhancer element is possibly regulating CCND1 in both humans and mice, opening the possibility of studying MYEOV regulatory functions in cancer using non-primate animal models.

genomics↗

bioRxiv2021

Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation. Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

cancer biology↗

bioRxiv2021

High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation

Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to genome 3D structure remains poorly understood. Here we used the highly-predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B-cells. After confirming that the model gives good predictions of Hi-C data for the non-malignant human B-cell derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy chain locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodelling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation break-points.

genomics↗

bioRxiv2020

Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with hijacking of super-enhancers of other common oncogenes in B-cell (MAF, MYC and FGFR3/NSD2) and T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.

genomics↗