Biology subjects

Oh, S. T.

Publications and source records attributed to Oh, S. T..

6 recordsLinked to original sources

bioRxiv2026

TNFα drives platelet hyperreactivity and thromboinflammation through regulation of hematopoietic stem and progenitor cells.

TNF is the primary age-related cytokine responsible for hyperreactive platelet formation. In mouse models, increased TNF induced abnormal megakaryocyte development and platelet activity. Here, we extend these findings to demonstrate that TNF drives this thrombotic phenotype through expansion of the hematopoietic stem and progenitor cell (HSPCs) compartment. Using HSPC-specific TNF receptor labeling and single cell RNA sequencing, we found that TNF receptors are absent from megakaryocytes and their progenitors (MkPs) indicating that TNF does not directly act on these cells. Chronic TNF exposure expanded HSPCs in the bone marrow and extramedullary tissues - and these expanded HSPCs retained functional repopulation capacity. Using species-specificity TNF receptor activation, we further demonstrate that TNFR1 signaling is sufficient to induce platelet hyperreactivity independent of HSPC expansion. Unlike emergency hematopoiesis, chronic TNF promoted megakaryopoiesis through the canonical hematopoietic hierarchy as demonstrated by lineage-tracing studies. Mechanistically, chronic TNF induced a distinct transcriptional program in single cell RNA sequencing of HSPCs and megakaryocytes. Together, these findings establish that chronic TNF promotes hyperreactive platelet formation not through direct effects on megakaryocytes or MkPs but by expanding and transcriptionally reprogramming HSPCs, thereby imprinting a TNF dependent program that persists through megakaryopoiesis and ultimately produces hyperreactive platelets.

cell biology↗

bioRxiv2025

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNF mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.

cancer biology↗

bioRxiv2025

Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation

Unfolded protein response (UPR) promotes protein homeostasis under endoplasmic reticulum stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that Fc{gamma}R- MPP3 generates erythroid lineage and Jak2V617F mutation leads to overproduction of erythroid cells by expanding Fc{gamma}R- MPP3. We showed that UPR signaling increases myeloid cell production through promoting Fc{gamma}R- MPP3 transition to granulocyte/macrophage progenitor producing Fc{gamma}R+ MPP3 at the expense of erythroid lineage via the XBP1 pathway. Under a disease condition, UPR signaling cooperates with Jak2V617F mutation and exacerbates disease phenotype in a mouse model of polycythemia vera (PV) through the ATF4 pathway. Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies. Key pointsO_LIUPR signaling promotes myeloid cell production at the expense of erythroid lineage in steady state. C_LIO_LIUPR signaling collaborates with Jak2V617F mutation and increases red blood cell production. C_LI

cell biology↗

bioRxiv2024

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

genomics↗

bioRxiv2020

A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are chronic blood diseases with significant morbidity and mortality. While sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically-engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDXs). These PDXs robustly engrafted patient cells which recapitulated the patients genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify MF patients at-risk for sAML transformation, and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology. STATEMENT OF SIGNIFICANCEAlthough the genetic events driving myeloproliferative neoplasms (MPNs) are well-defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a patient-derived xenograft (PDX) system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacological manipulation.

cancer biology↗

bioRxiv2018

Microglial Heterogeneity in a Mouse Model of Alzheimer’s Disease: A Mass Cytometry Analysis

Microglia, the resident immune cells of the central nervous system, have been subject to intense scrutiny recently because of their implicated role in the pathogenesis of Alzheimers disease, as well as many other neurological conditions. However, little is known about the diversity of microglial phenotypes, apart from the clear recognition that the M1-M2 distinction is an oversimplification. We used mass cytometry, a high dimensional analog of flow cytometry involving mass spectrometry-based analyses of single cells bound with metal-tagged antibodies, to characterize the diversity of microglia isolated from the brains of 3xTg-AD mice at 12, 18, and 24 months of age. Antibodies to microglial surface antigens CD11b, CD11c, CD14, CD18, CD24, CD35, CD38, CD45, CD51, CD64, CD68, CD86, CD124, CD172a, CD200R, CD206, CD274, CD301, CX3CR1, F4-80, MERTK, MHC class II, Siglec F, and TLR4 as well as intracellular antigens Arginase-1, IL10, IL12p40, iNOS, NADPH Oxidase, TGF-beta, and TNF-alpha were conjugated to unique metal isotopes, and used for mass cytometry. Phenograph-based clustering of the resulting high dimensional datasets identified 28 cell clusters of widely varying sizes, including clearly discrete phenotypes as well as pseudo-continuous/fractal phenotypic diversity. Monte Carlo simulations involving random reshuffling of the datasets revealed very different and much more uniform clustering patterns. Furthermore, control analyses of mouse peripheral blood mononuclear cells and brain microglia using the same markers revealed largely disjoint clusterings, indicating that these microglial clusters were not the result of peripheral blood contamination. Most of the microglial clusters were similar in samples from 3xTg-AD mice at all 3 ages, as well as from 12-month-old wild-type mice. The largest cluster expressed high levels of canonical microglial markers CD11b, CD11c, CD18, CD64, CD68, CD200R, CX3CR1, F4-80, NADPH oxidase, and TGF-beta but did not vary between experimental groups. However, 3 clusters did differ across experimental groups, one of which increased significantly with age in the 3xTg-AD mice as a fraction of the total microglial population. This cluster expressed high levels of CD18, CD38, CD45, CD86, and CD200R, but not other canonical markers. In summary, these mass cytometry-based analyses revealed previously uncharacterized microglial phenotypic heterogeneity in a mouse model of Alzheimers disease. The specific roles of the putative subclasses of microglia, their relevance to human disease, and many other questions remain to be addressed.

neuroscience↗