Biology subjects

Mitchell, O.

Publications and source records attributed to Mitchell, O..

5 recordsLinked to original sources

bioRxiv2026

Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis

Clonal Hematopoiesis (CH) affects the aging population and is associated with increased risk of hematological malignancy, cardiovascular disease, and all-cause mortality. Therapeutic options for CH remain limited. Using hematopoietic stem and progenitor cell (HSPC) color barcoding and mosaic mutagenesis in zebrafish, we identified perturbed choline metabolism and increased phosphatidylcholine (PC) biosynthesis via choline kinase alpha (CHKA) in asxl1-mutant HSPCs. Suppressing CHKA-dependent choline flux reduced ASXL1-driven clonal expansion. This effect was conserved in a murine DNMT3A and human TET2 model. Mechanistically, CHKA- dependent choline flux controls phosphatidylcholine production that supports platelet activating factor (PAF) production. Exogenous PAF overcomes the suppressive effect of CHKA inhibition in ASXL1 and TET2 models. We isolated primary, human HSPCs from the peripheral blood of patients with endogenous ASXL1 mutations and demonstrated that perturbing PAF signaling reduces their competitive potential in an ex vivo clonal competition assay. This CHKA/PAF axis is conserved in TET2-mutant HSPCs. Together, these findings identify a mutation agnostic metabolic dependency across the three most common CH genotypes and demonstrate that targeting the CHKA-dependent choline flux suppresses clonal expansion.

cancer biology↗

bioRxiv2025

Early life adversity and White Matter Microstructural Organization - a systematic review.

Early life adversity, defined as exposure to stressful events during childhood, is a significant risk factor for the development of psychiatric disorders. Diffusion tensor imaging studies employing tract-based spatial statistics have shown microstructural abnormalities in white matter among individuals exposed to early life adversity; however, robust conclusions are yet to be drawn. This systematic review synthesizes findings of previous tract-based spatial statistics studies to identify the white matter alterations in adult brains exposed to early life adversity, in papers with methodological consistency. The literature search (April 2024) was conducted to identify tract-based spatial statistics studies that compared diffusion metrics between adults exposed to early life adversity and adults not. Embase, Pubmed, and PsycInfo were searched, retrieving 2458 articles. Following deduplication, 1739 titles and/or abstracts were screened. 1699 articles were excluded, and 40 full texts were reviewed. Seven articles, reporting on 764 subjects, met the inclusion criteria and were included in the narrative synthesis. Compared to controls, adults exposed to early life adversity showed lower fractional anisotropy values in white matter tracts of the limbic and visual processing systems, specifically the anterior thalamic radiation, inferior longitudinal fasciculus, corona radiata, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulum bundle. This systematic review highlights that early life adversity may underlie emotional dysregulation and contribute to an increased risk of psychopathology in later life and explores the potential neurobiological mechanisms that underpin these structural changes. Understanding these associations is crucial for developing targeted interventions aimed at mitigating the long-term impact of early life adversity.

neuroscience↗

bioRxiv2024

Leukemia-derived apelin selects endothelial niche clones to promote tumorigenesis

Hematopoietic stem cells are regulated by endothelial and mesenchymal stromal cells in the marrow niche1-3. Leukemogenesis was long believed to be solely driven by genetic perturbations in hematopoietic cells but introduction of genetic mutations in the microenvironment demonstrated the ability of niche cells to drive disease progression4-8. The mechanisms by which the stem cell niche induces leukemia remain poorly understood. Here, using cellular barcoding in zebrafish, we found that clones of niche endothelial and stromal cells are significantly expanded in leukemic marrows. The pro-angiogenic peptide apelin secreted by leukemic cells induced sinusoidal endothelial cell clonal selection and transcriptional reprogramming towards an angiogenic state to promote leukemogenesis in vivo. Overexpression of apelin in normal hematopoietic stem cells led to clonal amplification of the niche endothelial cells and promotes clonal dominance of blood cells. Knock-out of apelin in leukemic zebrafish resulted in a significant reduction in disease progression. Our results demonstrate that leukemic cells remodel the clonal and transcriptional landscape of the marrow niche to promote leukemogenesis and provide a potential therapeutic opportunity for anti-apelin treatment.

cancer biology↗

bioRxiv2024

Bullying and Early Brain Development: A Longitudinal Structural Magnetic Resonance Imaging Study from Adolescence to Early Adulthood

This study investigated associations between bullying victimization and brain development using longitudinal structural MRI data from the IMAGEN cohort (n = 2,094; 1,009 females) across three time points ([~]14, [~]19, and [~]22 years). A data-driven analysis revealed that higher bullying victimization was significantly associated with accelerated volumetric growth in subcortical and limbic regions, including the putamen ({beta} = 0.12, 95% CI: 0.10-0.15), amygdala ({beta} = 0.07, 95% CI: 0.05-0.09), hippocampus ({beta} = 0.06, 95% CI: 0.04- 0.08), and anterior cingulate cortex (caudal: {beta} = 0.05, 95% CI: 0.03-0.07; rostral: {beta} = 0.06, 95% CI: 0.04-0.08). In contrast, bullying victimization was also significantly associated with reduced volumetric growth in the cerebellum ({beta} = -0.09, 95% CI: -0.11 to -0.07), entorhinal cortex ({beta} = -0.10, 95% CI: -0.13 to -0.07), and insula ({beta} = -0.08, 95% CI: -0.11 to -0.06).Exploratory analyses indicated that females exhibited more pronounced changes in emotional processing regions, while males showed greater changes in motor and sensory areas. Overall, the findings indicate that bullying victimization is associated with widespread structural differences in brain development from adolescence to early adulthood, with sex-specific trajectories.

neuroscience↗

bioRxiv2022

DNA Methylation Dynamics and Dysregulation Delineated by High-Throughput Profiling in the Mouse

We have developed a mouse Infinium DNA methylation array that contains 297,415 probes to capture the diversity of mouse DNA methylation biology. We present a mouse DNA methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, age, sex, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, PDX assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. ApcMin/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This MM285 mouse array is widely accessible to the research community, and will accelerate future high sample-throughput studies in this important model organism.

genomics↗