Implications of Clonal Hematopoiesis in Hematological and Non-Hematological Disorders

Abstract

Clonal hematopoiesis (CH) is associated with an increased risk of developing myeloid neoplasms (MNs) such as myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). In general, CH comprises clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). It is an age-related phenomenon characterized by the presence of somatic mutations in hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) that acquire a fitness advantage under selection pressure. Individuals with CHIP have an absolute risk of 0.5-1.0% per year for progressing to MDS or AML. Inflammation, smoking, cytotoxic therapy, and radiation can promote the process of clonal expansion and leukemic transformation. Of note, exposure to chemotherapy or radiation for patients with solid tumors or lymphomas can increase the risk of therapy-related MN. Beyond hematological malignancies, CH also serves as an independent risk factor for heart disease, stroke, chronic obstructive pulmonary disease, and chronic kidney disease. Prognostic models such as the CH risk score and MN-prediction models can provide a framework for risk stratification and clinical management of CHIP/CCUS and identify high-risk individuals who may benefit from close surveillance. For CH or related disorders, therapeutic strategies targeting specific CH-associated mutations and specific selection pressure may have a potential role in the future.

Keywords: acute myeloid leukemia; clonal cytopenia of undetermined significance; clonal hematopoiesis; clonal hematopoiesis of indeterminate potential; myelodysplastic neoplasm.

Figure 1

Progression and implications of clonal hematopoiesis. CH is initiated by the presence of driver mutations in the hematopoietic stem cells (HSCs). Those CH-related HSCs acquire a fitness advantage under selective pressures such as therapies like chemotherapy/radiation, smoking, and inflammation, which are risk factors that can promote the process of clonal expansion and malignant transformation. CH is associated with an increased risk of myeloid neoplasms. MDS: myelodysplastic neoplasm; MPN: myeloproliferative neoplasm; AML: acute myeloid leukemia.

Figure 2

Malignant and nonmalignant outcomes of CHIP. CHIP carriers have an increased risk of many malignant and nonmalignant disorders. The progression of hematological malignances cardiovascular disease, COPD, and chronic liver disease is mostly related to CHIP, but CHIP carriers are associated with a decreased risk of Alzheimer’s disease.