Clonal hematopoiesis of indeterminate potential: a multisystem hub bridging hematopoietic dysfunction with non-hematopoietic diseases.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), driven by leukemia-related somatic mutations in hematopoietic stem cells, previously recognized as a major risk factor for hematological malignancies, has now emerged as a potent risk factor for chronic inflammation and diverse non-hematologic diseases. CHIP-associated DNA methyltransferase 3 alpha (DNMT3A), tet methylcytosine dioxygenase 2 (TET2), and additional sex combs like 1 (ASXL1) mutations alter epigenetic programs, skew myelopoiesis, and increase proinflammatory cytokines, resulting in chronic inflammation and immune imbalance. This review integrates mechanistic insights with clinical evidence to delineate CHIP's roles in solid tumors, cardiovascular disorders, and metabolic dysregulation, with an extended discussion of renal dysfunction and neurodegenerative conditions. Furthermore, we also discuss CHIP's diagnostic and therapeutic impacts across multiple disease contexts, advocating for mutation-specific diagnostic paradigms to guide therapeutic interventions.