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Uncovering the Link Between Clonal Hematopoiesis and Chronic Obstructive Pulmonary Disease
Peter Miller, MD, PhD, from Massachusetts General Hospital and Harvard Medical School, is working to further uncover the role of clonal hematopoeisis in COPD.
Peter Miller, MD, PhD, Assistant Professor of Medicine at Massachusetts General Hospital and Harvard Medical School, is conducting groundbreaking research to elucidate the role of clonal hematopoiesis (CH) in chronic obstructive pulmonary disease (COPD), with a particular emphasis on somatic mutations in the ASXL1 gene. COPD, a progressive lung disease resulting in airflow limitation, remains a leading cause of morbidity and mortality and is the fourth leading cause of death in the United States.1,2
Though advancing treatment options have improved outcomes in individuals with COPD, prevention and risk stratification for both disease onset and progression remain unmet needs. Efforts to better define factors that contribute to the development and progression of COPD are therefore needed. The pathogenic drivers of COPD, which include both adaptive and innate immune signaling and characterized by enhanced inflammation, remain incompletely understood.3-5 Risk factors for developing COPD can be broadly categorized as age-related, environmental, and genetic. The strongest environmental risk factor remains cumulative cigarette smoke(CS) exposure.1 The genetic contributors for development of COPD have been almost exclusively related to germline risk, including monogenic risk alleles, such as alpha-1 antitrypsin deficiency, and polygenic risk contribution.6-8
Recent investigations led by Dr. Miller have uncovered a previously unrecognized association between clonal hematopoiesis—characterized by somatic mutations in hematopoietic stem cells—and an increased risk of developing COPD, independent of conventional risk factors such as cigarette smoke exposure and inherited genetic variants.9
CH is a very common, age-associated condition, with up to 10% of individuals by the age of 60-70 having large mutant clones in the peripheral blood.10 Specifically, mutations in ASXL1, the third most frequently mutated gene in CH, have been identified as significant contributors to inflammatory pathways involved in COPD.11-14 These ASXL1 mutations disrupt normal chromatin remodeling and gene regulation, promoting inflammatory responses in blood cells, notably macrophages. Dr. Miller's preliminary data strongly suggest that individuals harboring ASXL1 mutations exhibit higher susceptibility to COPD.
To rigorously test and expand upon these findings, Dr. Miller's proposal integrates 2 comprehensive aims designed to address critical gaps in current knowledge. First, through extensive genetic epidemiological studies involving approximately 500,000 participants from prominent biobanks such as the UK Biobank, TOPMed, and Massachusetts General Brigham, the research will systematically quantify the association between ASXL1-mutant CH and COPD. This analysis will pinpoint genetic modifiers, particularly inflammatory gene variants, which may intensify disease risk. The research further seeks to characterize distinct clinical COPD phenotypes associated with ASXL1 mutations, such as frequency and severity of exacerbations and specific radiological manifestations of emphysema.
Second, leveraging cutting-edge mouse models, Dr. Miller's team will experimentally confirm these epidemiological findings and delve deeper into the mechanistic roles of ASXL1 mutations in driving COPD pathogenesis. By engineering mice to express ASXL1 mutations selectively in hematopoietic cells and subsequently exposing them to cigarette smoke, the team aims to closely mimic the human disease environment. Detailed analyses of emphysema severity, inflammatory responses, and cellular changes within lung tissues will be conducted using advanced methodologies like single-cell RNA sequencing. Furthermore, the therapeutic potential of inflammatory blockade will be rigorously evaluated, potentially offering innovative avenues for COPD management.
This integrated research approach uniquely positions Dr. Miller's work at the forefront of pulmonary medicine, bridging disciplines of hematology and pulmonology while utilizing state-of-the-art genetic and genomic tools to uncover novel inflammatory mechanisms in COPD. Outcomes from this study hold considerable promise for reshaping our understanding of COPD, significantly enhancing risk prediction, and opening pathways to groundbreaking preventative and therapeutic interventions.
Miller has no relevant disclosures to report.
