Concise Review: Age-Related Clonal Hematopoiesis: Stem Cells Tempting the Devil

Abstract

The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non-driver candidates. These mutations are present at low frequency in the majority of individuals after middle-age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%-40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality. Blood cell parameters appear unmodified in these individuals, but a minority of them will develop a hematologic malignancy. At this time, the factors put forward as potentially influencing the risk of cancer development are clone size, specific gene, specific mutation, and the number of mutations. Specific stress on hematopoiesis also gives rise to clonal expansion. Genotoxic exposure (such as chemotherapy), or immune attack (as in aplastic anemia) selects/provides a fitness advantage to clones with a context-specific signature. Clonal hematopoiesis offers a new opportunity to understand the biology and adaptation mechanisms of aging hematopoiesis and provides insight into the mechanisms underlying malignant transformation. Furthermore, it might shed light on common denominators of age-associated medical conditions and help devise global strategies that will impact the prevention of hematologic cancers and promote healthy aging. Stem Cells 2018;36:1287-1294.

Keywords: Aging; Hematologic malignancies; Hematopoiesis; Stem cells.

Figure 1

Panel A. Evolution of CHIP in the aging population. Mutations begin to appear in middle-aged subjects at a low frequency. In a subset of subjects (10–40%), the clone will expand to meet diagnostic criteria of CHIP (VAF>2%). Factors influencing clonal expansion are enumerated in Table 2 and include inflammation. Fitness of wild type (WT) HSC may be key in maintaining polyclonal hematopoiesis. Blood counts remain normal in polyclonal and CHIP individuals. A small proportion of subjects with CHIP will progress to hematological cancer under the influences enumerated in Table 3. A proportion of subjects with CHIP will develop cardiovascular disease. Subjects without CHIP may also develop hematological cancers or cardiovascular disease but have a lower relative risk. Panel B. Specific mutations such as TP53 or PPM1D may provide HSC with resistance to genotoxic stress such as chemotherapy or radiotherapy and promote clonal expansion. These mutations may lead to development of t-AML. Panel C. Immune attack of HSC promotes selection of cells with a mutational profile different than that of aging or genotoxic stress. In younger patients this includes mutations in PIGA, BCOR/BCORL1 and HLA deletions. In older subjects, mutations in DNMT3A and ASXL1 are also documented, but TET2 mutations are underrepresented.