Biology subjects

Trowbridge, J.

Publications and source records attributed to Trowbridge, J..

6 recordsLinked to original sources

bioRxiv2026

Neutrophil-Derived S100A8/A9 Drives Inflammation that Promotes Dnmt3a -Mutant Hematopoiesis

Clonal hematopoiesis (CH) is an age-associated condiion defined by over-representation of hematopoietic stem cells (HSCs) and their progeny carrying somatic mutations or variants that confer a selective advantage. CH is associated with increased risk of hematologic malignancies (1), cardiovascular disease and inflammatory bone loss (2, 3). Chronic inflammation is increasingly recognized as a central mediator of CH-mutant hematopoietic stem and progenitor cell (HSPC) expansion underlying CH (4). DNA methyltransferase 3a ( Dnmt3a )-mutant cells produce higher levels of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) (5), and blocking these pathways reduces the competitive advantage of Dnmt3a -mutant HSPCs (4, 6). The upstream mediators initiating inflammatory signaling in CH are unknown. Strong candidates are S100A8 and S100A9, members of the S100 calcium-binding protein family that regulate inflammatory signaling in the hematopoietic system. These proteins form a heterodimer complex and activate innate immune signaling through receptors including Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) (7). S100A8/A9 signaling promotes production of pro-inflammatory cytokines and inflammasome activation leading to poor prognosis in myelodysplastic syndrome and myeloproliferative neoplasms (8, 9). Across multiple myeloid malignancies, neutrophils are the primary bone marrow (BM) source of this alarmin (8, 10, 11) and pharmacologic inhibition of S100A9 with tasquinimod reduces disease severity without disrupting normal hematopoiesis (10, 12). Given the role of S100A8/A9 in establishing an inflammatory milieu, here we investigated the role of S100A8/A9 in Dnmt3a -mutant hematopoiesis. We identify neutrophils as a major source of elevated S100A8/A9 in the BM of Dnmt3a -mutant mice and this increase correlates with production of the inflammatory cytokines TNFα and IL-6. We show that tasquinimod reduces TNFα and IL-6 levels and selectively reduces the Dnmt3a -mutant HSPC compartment.

Cell Biology↗

bioRxiv2025

Functional Equivalence of Gamma- and X-Ray Irradiation for Long-Term Hematopoietic and AML Transplant Outcomes in Mice

Total-body irradiation (TBI) is routinely used for myeloablation prior to mouse hematopoietic cell transplant. Widespread transition from 137Cs{gamma} -irradiators to X-ray systems has raised questions about whether these modalities yield equivalent biological outcomes. Although prior studies compared{gamma} and X-ray irradiation in healthy syngeneic transplants, their performance in reciprocal congenic models and in primary acute myeloid leukemia (AML) transplant remains unclear. Here, we systematically evaluated{gamma} and X-ray irradiation across dose and dose-rate conditions, and tested dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. While each modality exhibited distinct early effects, both ultimately supported comparable long-term donor chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression. These findings indicate that, with proper dose calibration, X-ray irradiation is a functionally effective alternative to{gamma} -irradiation for normal and malignant transplant studies.

cell biology↗

bioRxiv2025

An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NF{kappa}B, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

cell biology↗

bioRxiv2020

Heritable Genetic Background Alters Survival and Phenotype of Mll-AF9-Induced Leukemias

The MLL-AF9 fusion protein occurring as a result of t(9;11) translocation gives rise to pediatric and adult acute leukemias of distinct lineages, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). The mechanisms underlying how this same fusion protein results in diverse leukemia phenotypes among different individuals is not well understood. Given emerging evidence from genome-wide association studies (GWAS) that genetic risk factors contribute to MLL-rearranged leukemogenesis, here we tested the impact of genetic background on survival and phenotype of a well-characterized Mll-AF9 knockin mouse model. We crossed this model to five distinct inbred strains (129, A/J, C57BL/6, NOD, CAST), and tested their F1 hybrid progeny for dominant genetic effects on Mll-AF9 phenotypes. We discovered that genetic background altered peripheral blood composition, with Mll-AF9 CAST F1 demonstrating significantly increased B lymphocyte frequency while the remainder of the strains exhibited myeloid-biased hematopoiesis, similar to the parental line. Genetic background also impacted overall survival, with Mll-AF9 A/J F1 and Mll-AF9 129 F1 having significantly shorter survival, and Mll-AF9 CAST F1 having longer survival, compared to the parental line. Furthermore, we observed a range of hematologic malignancies, with Mll-AF9 A/J F1, Mll-AF9 129 F1 and Mll-AF9 B6 F1 developing exclusively myeloid cell malignancies (myeloproliferative disorder (MPD) and AML) whereas a subset of Mll-AF9 NOD F1 developed MPAL and Mll-AF9 CAST F1 developed ALL. This study provides a novel in vivo experimental model to evaluate the underlying mechanisms by which MLL-AF9 results in diverse leukemia phenotypes and provides definitive experimental evidence that genetic risk factors contribute to survival and phenotype of MLL-rearranged leukemogenesis.

cancer biology↗

bioRxiv2019

Aging-Associated Decrease in the Histone Acetyltransferase KAT6B Causes Myeloid-Biased Hematopoietic Stem Cell Differentiation

Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused shRNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is most highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as an epigenetic regulator of LT-HSC aging and a novel target to improve aged immune function.

cell biology↗

bioRxiv2019

Integrating exposure knowledge and serum suspect screening as a new approach to biomonitoring: An application in firefighters and office workers

BackgroundWomen firefighters are exposed to recognized and probable carcinogens, yet there are few studies of chemical exposures and associated health concerns, such as breast cancer. Biomonitoring often requires a priori selection of compounds to be measured, and so may not detect important, lesser known, exposures.\n\nObjectivesThe Women Firefighters Biomonitoring Collaborative (WFBC) created a biological sample archive and conducted a general suspect screen (GSS) to address this data gap.\n\nMethodsUsing liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) we sought to identify candidate chemicals of interest in serum samples from 83 women firefighters (FF) and 79 office workers (OW) in San Francisco. Through the GSS approach we identified chemical peaks by matching accurate mass from serum samples against a custom chemical database of 740 slightly polar phenolic and acidic compounds, including many of relevance to firefighting or breast cancer etiology. We then selected chemicals for confirmation based on a priori criteria: 1) detection frequency or peak area differences between OW and FF; 2) evidence of mammary carcinogenicity, estrogenicity, or genotoxicity; and 3) not currently measured in large biomonitoring studies.\n\nResultsWe detected 620 chemicals that matched 300 molecular formulas in the WFBC database, including phthalate metabolites, phosphate flame retardant metabolites, phenols, pesticides, nitro-and nitroso-compounds, and per- and polyfluoroalkyl substances. The average number of chemicals from the database that were detected in participants was 72 and 70 in FF and OW, respectively. We confirmed 8 of the 20 prioritized suspect chemicals -including two alkylphenols, ethyl paraben, BPF, PFOSAA, benzophenone-3, benzyl p-hydroxybenzoate, and triphenyl phosphate--by running a matrix spike of the reference standards and using m/z, retention time and the confirmation of at least two fragment ions as criteria for matching.\n\nConclusionGSS provides a powerful high-throughput approach to identify and prioritize novel chemicals for biomonitoring and health studies.

epidemiology↗