Multiomic profiling of human clonal hematopoiesis reveals genotype and cell-specific inflammatory pathway activation

Area of Science:

• Hematology
• Immunology
• Genetics

Background:

• Clonal hematopoiesis (CH) is linked to increased risks of hematologic malignancy and cardiovascular disease.
• Inflammation in peripheral blood is a proposed mechanism driving CH-associated risks.

Purpose of the Study:

• To investigate the molecular mechanisms underlying CH-associated inflammation.
• To compare gene expression profiles of mutant and non-mutant cells in CH patients.

Main Methods:

• Single-cell RNA sequencing of peripheral blood from 17 CH patients and 7 controls.
• Novel mitochondrial DNA barcoding to distinguish mutant (TET2, DNMT3A) and non-mutant cells.
• Analysis of gene expression in myeloid and T-cell compartments.

Main Results:

• The majority of mutated cells were identified in the myeloid compartment.
• CH patients with DNMT3A/TET2 mutations showed a proinflammatory profile in CD14+ monocytes via galectin and macrophage inhibitory factor pathways.
• T cells from CH patients exhibited decreased expression of immunity-associated GTPase genes, suggesting impaired T-cell function.

Conclusions:

• CH is associated with distinct proinflammatory pathways in monocytes and impaired T-cell function.
• These findings provide novel insights into CH pathogenesis and its systemic effects.
• Targeting these pathways may offer therapeutic strategies for CH-related complications.