Clonal hematopoiesis and risk for hematologic malignancy

Abstract

Clonal hematopoiesis (CH) is common in older persons and is associated with an increased risk of hematologic cancer. Here, we review studies establishing an association between CH and hematopoietic malignancy, discuss features of CH that are predictive of leukemic progression, and explore the role of hematopoietic stressors in the evolution of CH to acute myeloid leukemia or myelodysplastic syndrome. CH due to point mutations or structural variants such as copy-number alterations is associated with an ∼10-fold increased risk of hematopoietic malignancy. Although the absolute risk of hematopoietic malignancy is low, certain features of CH may confer a higher risk of transformation, including the presence of TP53 or spliceosome gene mutations, a variant allele fraction >10%, the presence of multiple mutations, and altered red blood indices. CH in the setting of peripheral blood cytopenias carries a very high risk of progression to a myeloid malignancy and merits close observation. There is emerging evidence suggesting that hematopoietic stressors contribute to both the development of CH and progression to hematopoietic malignancy. Specifically, there is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from CH to a myeloid malignancy. Models that incorporate features of CH along with an assessment of hematopoietic stressors may eventually help predict and prevent the development of hematopoietic malignancies.

Graphical abstract

Figure 1.

Model of MDS/AML pathogenesis in SDS, Li Fraumeni syndrome, and tMN. In Li Fraumeni syndrome, all of the HSPCs carry heterozygous TP53 mutations (indicated by blue/red shaded cells). In the absence of genotoxic stress (eg, chemotherapy), there is no selective pressure to mutate the second allele. Thus, MDS/AML in Li Fraumeni syndrome is uncommon. In SDS, mutations of SBDS lead to chronic ribosome stress, which can select for HSPCs that have mutated 1 allele of TP53 and result in TP53-mutated CH. Continued ribosome stress then selects for HSPCs in which both TP53 alleles are mutated (red shaded cells), which ultimately leads to MDS/AML. Patients undergoing treatment with cytotoxic chemotherapy or radiation experience significant genotoxic stress, resulting in selection of HSPCs carrying age-related TP53 mutations. In this model, repeated exposure to cytotoxic therapy selects for HSPCs carrying biallelic TP53 mutations, which ultimately leads to MDS/AML. Other hematopoietic stressors, such as chronic inflammation, may promote progression from CH to myeloid malignancy in a similar fashion by providing a fitness advantage to HSPCs carrying mutations in other genes besides TP53. tAML, therapy-related AML; tMDS, therapy-related MDS.