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Etiology of Acute Myeloid Leukemia: Clonal Hematopoiesis

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P940-941

2026-10-06

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HSCs acquire somatic mutations with age. Mutations that confer a fitness advantage create a state of clonal hematopoiesis (CH) in which a clonally derived population of cells can be detected in peripheral blood or bone marrow. CH is nearly ubiquitous in the adult population when very sensitive error corrected sequencing technologies are used. Using more stringent thresholds typically employed in routine clinical sequencing (i.e., variant allele fraction of 2%), CH is detectable in nearly 10% of apparently healthy individuals older than 65 years of age. This is termed clonal hematopoiesis of indeterminate potential (CHIP) if the affected individual has normal blood counts and no ante cedent hematologic malignancy. In contrast, CH in patients with idiopathic cytopenias but without a morphologically apparent hematologic malignancy is referred to as clonal cytopenias of undetermined significance (CCUS). The genes most frequently mutated in CHIP and CCUS encode epigenetic regulators (e.g., DNMT3A, TET2, ASXL1) which are also targets of recurrent mutations in MDS/AML.

Patients with CHIP carry a small but significantly increased risk of progression to overt hematologic malignancy, approximately 0.5% to 1% per year, most often to MDS or AML. The risk of progression to a hematologic malignancy is higher in individuals with CCUS, a large clone size, more than one driver mutation, and mutations in specific genes (particularly, spliceosome components). Patients with CH also have a significantly increased risk of cardiovascular events, typically atherosclerosis-related vascular events, possibly related to altered proinflammatory signaling in clonally derived monocytes, among other mechanisms. Additional epidemiologic study will be required to determine how often CH is a precursor to MDS/AML and whether surveillance and/or early intervention are warranted.