Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity

Abstract

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), defined as the presence of a somatic mutation in the peripheral blood at a variant allele frequency (VAF) ≥2%, affects at least 10% of individuals older than 65, but low-VAF clones can be detected in 95% of individuals older than 50. CHIP associates with a wide range of comorbidities from atherosclerosis to pulmonary disease. A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities. Mutant leukocytes from animal models contribute to an inflammatory milieu that may confer a selective advantage to the clone, thus perpetuating a cycle of inflammation and expansion. Although it is unclear whether inflammation or expansion sets this cycle in motion, some evidence suggests that inflammation from infections or pre-existing comorbidities initiates this cycle. The pro-inflammatory phenotypes of macrophages from mutant clones and their contributions to disease are well characterized in murine models, but have not yet been confirmed in humans. Furthermore, the roles of other cell types that can carry mutations of CHIP are not fully understood. We propose a rationale for further investigation of neutrophils, other granulocytes and T, B, and NK cells as they may play a role in CHIP-associated comorbidities. As the understanding of CH has advanced, potential interventions, especially those targeting aberrant inflammation, have been proposed. We are hopeful that as studies continue to unravel the complex links between CHIP, inflammation, and leukocyte dysfunction, CHIP-related comorbidities may be more effectively managed.

Clinico-Biological Features and Clonal Hematopoiesis in Patients with Severe COVID-19

“…Most reports use a VAF of at least 2% to define CHIP, which represents the sensitivity threshold of current HTS technologies used in the clinical setting [20]. Sequencing data variability and threshold of our HTS technology were determined by serial sequencing of the multiplex NGS Tru-Q DNA 7 (Horizon Diagnostics, Cambridge, UK).…”

Elevated expression of clonal hematopoiesis of indeterminate potential in patients with coronary endothelial dysfunction is associated with future cardiovascular events

“…The underlying mechanisms of the link between CHIP and cardiovascular diseases are being sought in cardiovascular research. It has been suggested that CHIP associated mutations can alter transcription of genes related to in ammatory pathways in peripheral blood cells such as monocytes, potentially augmenting in ammatory responses during the atherogenesis (10). Murine models of TET2 and DNMT3A loss-of-function mutations showed advanced cardiovascular diseases, potentially through accelerating in ammation (31).…”

“…Prior studies on CHIP (7-9) have focused on late stages of atherosclerosis and there is a lack of data to show the impact of CHIP on endothelial dysfunction, which can also be impaired by prevalent in ammation. Yet, patients with mutations in DNMT3A or TET2 are at higher risk of cardiovascular diseases, which is linked to IL-6 receptor activation (10,11). TET2 de cient-cells have also showed increased transcription of IL-6 via alternation in histone deacetylation (12).…”

The Role of Autoimmune Diseases in the Prognosis of Lymphoma

“…In more than half of them, death was caused by adverse events, such as infection and the development of a therapy-related neoplasm. It is interesting to note that the association between CHIP and inflammation is not confirmed for every inflammatory condition, e.g., RA, which could indicate a potential role of anti-inflammatory drugs in suppressing CH [17]. Therefore, further examination of the complex biological processes (responsible for both conditions) could lead to a better understanding of the clinical pathologies, thus increasing the possibility of adopting a specialized medicine approach.…”