Comorbid associations, inflammatory and immune-related aberrations of clonal hematopoiesis of indeterminate potential

Abstract

To ascertain the prevalence of pre-cancerous blood cell mutations, we recruited and performed targeted next-generation sequencing of peripheral blood of a hematologically-healthy cohort (n=359) of adults >65 years. We detected somatic mutations in a remarkable 23% overall, with age-dependent increase, and acquired most often in the myeloid cancer-associated genes DNMT3A and TET2. We hypothesized that this phenomenon, now referred to as clonal hematopoiesis of indeterminate potential (CHIP), occurs in the context of selective pressures (i.e. disease/inflammation) exerted on mutant clones, and that the progeny of these clones contribute to ill health. In keeping, we found an increased burden of comorbidities and increased ECOG-PS scores indicating frailty among people with CHIP. We also found prominent elevations in pro-inflammatory drivers, especially IL-6, in the blood serum of those with CHIP. Next, we profiled human blood cells with RNA-sequencing and found elevated expression of granulocyte granule content components in people with CHIP and confirmed the elevation of MPO and LTF protein in the serum. Additionally, we showed that people with CHIP are at increased risk of death from infection in the UK Biobank, but an MPO promoter single nucleotide polymorphism (associated with decreased MPO expression) mitigates this risk. The identified granule content components are most prominent in neutrophils, suggesting that neutrophil biology is perturbed in the context of CHIP. Functional assays with murine bone marrow-derived, Tet2-deficient neutrophils found them profoundly hindered in antimicrobial function in vitro. To investigate aberrant signaling in these cells, we performed additional RNA-sequencing, and found that at baseline, Tet2-deficient neutrophils have active interferon response-related transcription. Thus, we found CHIP is common with aging, associated with a pro-inflammatory systemic environment, comorbidities and ill health. People with CHIP are at increased risk of death from infection, which may relate to dysregulated neutrophil function via increased MPO, poor antimicrobial function, and aberrant interferon-related signaling. CHIP is emerging as an independent, common risk factor for numerous common comorbidities, and the dysfunctional neutrophil biology we have uncovered may have broader impact beyond infectious disease risk. Therapies that target the clones, inflammation, or aberrant neutrophils, may help alleviate the burden of disease in older adults.