CHIP ahoy: charting a decade of discovery in clonal hematopoiesis.

Clonal hematopoiesis (CH) involves the expansion of hematopoietic stem cells with ageacquired mutations linked to myeloid malignancy. Advances in next-generation and single-cell sequencing, along with computational modeling, have expanded our ability to detect both common and rare CH drivers, including single-nucleotide variants and mosaic chromosomal alterations, with increasing sensitivity. While sequencing methods differ in accuracy, cost, and ability to detect low-frequency variants, they have deepened our understanding of CH biology.

Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension.

Background And Aims: Multiple germline gene variants promote familial and idiopathic pulmonary arterial hypertension (PAH); however, none are consistently identified in associated PAH with connective tissue disease (APAH-CTD). Moreover, the role of somatic variants in genes mediating clonal haematopoiesis of indeterminate potential (CHIP) in PAH is unknown. Here, somatic and germline DNMT3A variants and CHIP gene variants in PAH were evaluated.

TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice.

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow.

Tet Methylcytosine Dioxygenase 2 (TET2) Mutation Drives a Global Hypermethylation Signature in Patients With Pulmonary Arterial Hypertension (PAH): Correlation With Altered Gene Expression Relevant to a Common T Cell Phenotype.

Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation/demethylation can promote the development of pulmonary arterial hypertension (PAH). Here, we performed epigenome-wide mapping of DNA methylation in whole blood from 10 healthy people and 19 age/sex-matched PAH patients from the PAH Biobank.

Multiplex PCR for the Rapid Diagnosis of Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPN) develop as a disease of aging, due to the disruption of normal hematopoiesis, triggered by somatic mutations and a sustained inflammatory cycle. Driving variants within JAK2, MPL, and CALR are associated with various subtypes of MPN, with known targeted therapeutics and guided patient prognosis. Targeted clinical testing for the diagnosis of these precise driving variants within these key genes has an integral role for personalized medicine.

Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes.

Clonal hematopoiesis (CH)-the expansion of somatically mutated hematopoietic cells-is common in solid cancers. CH is associated with systemic inflammation, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naive patient samples from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort.

Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.

The precancerous expansion of hematopoietic cells, termed clonal hematopoiesis (CH), has been correlated to disease development and all-cause mortality. Despite multiple observations that hematopoietic stem cell and progenitors (HSPCs) are significantly affected by both sex and age, there remain few studies quantifying male and female HSPC populations in wild-type and transgenic Tet2 models over time. Here, we determine that male mice (with a hematopoietic deficiency of Tet2 and control) have more LinSca-1c-kit (LSK) cells, that include multipotent progenitor cells (MPPs; LSK CD48CD150) and long-term hematopoietic stem cells (LT-HSC; LSK CD48CD150) compared with females.

Association of Omega-3 Status With Long-Term Risk of Hospitalization for Sepsis.

Objectives: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. Despite decades of clinical trials, there are no specific treatments; care of the nearly 50 million annual cases worldwide is limited to antimicrobials and supportive measures. A primary prevention strategy may therefore be of value.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than (non- CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes.

Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI.

Clonal hematopoiesis of indeterminate potential-associated non-small cell lung cancer risk is potentiated by small particulate matter air pollution among non-smokers: a novel somatic variant-environment interaction.

Small particulate matter air pollution (PM ) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smoking individuals. Inhaled PM recruits pro-inflammatory macrophages to the air-lung interface, which promotes malignant lung epithelial cell growth and progression to overt cancer. We sought to determine whether clonal hematopoiesis of indeterminate potential (CHIP), a common age-related condition characterized by hyperinflammatory macrophages, exacerbates PM -associated NSCLC in non-smokers using genetic, environmental, and phenotypic data from 413,901 individuals in the UK Biobank.

Germline and Somatic Mutations in DNA Methyltransferase 3A Predispose to Pulmonary Arterial Hypertension (PAH) in Humans and Mice: .

Background: Mutations are found in 10-20% of idiopathic PAH (IPAH) patients, but none are consistently identified in connective tissue disease-associated PAH (APAH), which accounts for ∼45% of PAH cases. mutations, a cause of clonal hematopoiesis of indeterminant potential (CHIP), predispose to an inflammatory type of PAH. We now examine mutations in another CHIP gene, , in PAH.

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases.

DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation, and their dysregulation is both a pathogenic mechanism of disease and a therapeutic target. DNMTs change gene expression by methylating CpG islands within exonic and intergenic DNA regions, which typically reduces gene transcription.

Clonal haematopoiesis, ageing and kidney disease.

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease.

Clonal Hematopoiesis: Updates and Implications at the Solid Tumor-Immune Interface.

Recent larger-scale studies of patients with cancer and longitudinal population cohorts have revealed how age-related expansions of mutant hematopoietic cells (clonal hematopoiesis [CH]) have differential associations with incident and prevalent cancers and their outcomes. Increasing recognition and deeper understanding of genetic subtypes of CH are yielding insights into the tumor-immune interface that may help to explain the heterogeneous impact of CH on tumorigenesis and treatment. Herein, we update the expanding influence of CH in precision oncology and propose important research and clinical questions to address to effectively manage and harness CH in oncology patients.

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation.

A DNA methylation based measure outperforms circulating CRP as a marker of chronic inflammation and partly reflects the monocytic response to long-term inflammatory exposure: A Canadian Longitudinal Study on Aging analysis.

A key hallmark in the age-related dysfunction of physiological systems is disruption related to the regulation of inflammation, often resulting in a chronic, low-grade inflammatory state (i.e., inflammaging).

COVID-19 and the Genetics of Inflammation.

Objective: Interindividual variability in the clinical progression of COVID-19 may be explained by host genetics. Emerging literature supports a potential inherited predisposition to severe forms of COVID-19. Demographic and inflammatory characteristics of COVID-19 suggest that acquired hematologic mutations leading to clonal hematopoiesis (CH) may further increase vulnerability to adverse sequelae.