Publications by authors named "Katherine Y King"

Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota-derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics.

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Here, we investigate the contribution of long-term hematopoietic stem cells (HSCs) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI.

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Article Synopsis
  • Interferon gamma (IFNγ) is a proinflammatory cytokine that can cause bone marrow failure by activating and exhausting hematopoietic stem cells (HSCs), with bone marrow stromal antigen 2 (BST2) playing a crucial role in this activation process.
  • Research using a murine model shows that knocking out BST2 doesn't impact immune responses or HSC localization in the bone marrow, but it does affect lipid raft polarity in response to IFNγ.
  • The study concludes that BST2 is essential for HSC division by promoting cell polarization and essential ERK1/2 activation, which could be significant for future cancer and bone marrow failure treatment strategies.
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  • Haematopoietic stem cells are crucial for lifelong blood production and were studied in young and old mice to understand how these cells change with age.
  • Researchers found that mouse stem cells accumulate about 45 somatic mutations per year, which is not drastically different from humans, despite their size and lifespan differences.
  • The study revealed that while stem cells independently maintain their populations throughout life, aged mice showed different patterns of clonal diversity and expansion compared to humans, particularly after blood system disturbances.
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It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5 ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5 ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome.

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Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus.

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Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation to safeguard the lung from spontaneous alveolar destruction and fibrosis.

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Article Synopsis
  • * A study identified changes in intestinal microbiota and metabolites in patients who developed neutropenia after antibiotic treatment; this disruption may affect blood cell production.
  • * No link was found between neutropenia and the type of infection or antibiotic used, but factors like ICU admission and longer treatment duration were associated with increased risk.
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Quiescence and differentiation of hematopoietic stem and progenitor cells (HSPC) can be modified by systemic inflammatory cues. Such cues can not only yield short-term changes in HSPCs such as in supporting emergency granulopoiesis but can also promote lasting influences on the HSPC compartment. First, inflammation can be a driver for clonal expansion, promoting clonal hematopoiesis for certain mutant clones, reducing overall clonal diversity, and reshaping the composition of the HSPC pool with significant health consequences.

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Over the past 10 years, there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady-state blood production, affecting both hematopoietic stem and progenitor cells as well as differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis.

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'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19.

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Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to infection.

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Chronic inflammation, although subtle, puts the body in a constant state of alertness and is associated with many diseases, including cancer and cardiovascular diseases. It leads hematopoietic cells to produce and release proinflammatory cytokines, which trigger specific signaling pathways in hematopoietic stem cells (HSCs) that cause changes in proliferation, differentiation, and migration. This response is essential when HSCs are needed to produce specific blood cells to eliminate an intruder, such as a pathogenic virus, but mutant HSCs can use these proinflammatory signals to their advantage and accelerate the development of hematologic disease or malignancy.

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Tumors protect themselves from immune clearance by promoting extramedullary hematopoiesis. A new study in PLOS Biology provides insights into the mechanisms underlying this process, which may hold the key to disrupting generation of the immunosuppressive tumor microenvironment.

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Article Synopsis
  • BATF2 is a protein that helps control how certain immune cells develop, especially during long-term infections.
  • When researchers looked at mice without BATF2, they noticed these mice had fewer signals that recruit immune cells and better kept their blood stem cells.
  • The study shows how BATF2 works with another protein to increase immune responses, and it suggests ways to help the immune system while protecting blood stem cells during infections.
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Chimeric antigen receptor (CAR) T cell (CAR-T) therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from the release of proinflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias, and those with the most severe CRS also have the longest delays in full marrow recovery.

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Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward.

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Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of all immune and blood cells in both steady state and emergency settings. The rates at which HSPCs divide and differentiate vary widely in accordance with both cell intrinsic and cell extrinsic factors. However, the kinetics of these events remain poorly understood.

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Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age and is associated with increased risks of cancers, cardiovascular disease, and other maladies. Here, we discuss how environmental contexts associated with CHIP, such as old age, infections, chemotherapy, or cigarette smoking, alter tissue microenvironments to facilitate the selection and expansion of specific CHIP mutant clones. Further, we consider major remaining gaps in knowledge, including intrinsic effects, clone size thresholds, and factors affecting clonal competition, that will determine future application of this field in transplant and preventive medicine.

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Unlabelled: Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress.

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Article Synopsis
  • Sepsis is a serious condition that causes one in five deaths worldwide, and new treatments are urgently needed.
  • Researchers studied how special blood cells called hematopoietic stem and progenitor cells (HSPCs), which help produce blood and immune cells, could help treat sepsis.
  • In mice with a type of sepsis, giving them extra HSPCs improved their survival by about 50-60%, and these cells helped reduce inflammation without affecting the amount of bacteria in their bodies.
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Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined.

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Background: We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low.

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Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras.

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