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Page 4 of 12 Solimando et al. J Cancer Metastasis Treat 2022;8:9 https://dx.doi.org/10.20517/2394-4722.2021.166

Functionally, clonal hematopoiesis and stem cell fitness in clinical and biological contexts have been
inspired by HSC transplant-derived data, obtained in a context where the cells with self-renewal potential
can engraft into the recipient, recapitulating the entire hematopoiesis. In this context, specific mutations or
clones with certain mutations may hold a given stem cell fitness, leading to the expansion of a specific
clone . Screening 1727 donors, Gibson et al. identified 388 subjects with clonal hematopoiesis, DNMT3
[26]
[26]
being the most commonly mutated gene followed by TET2 and other mutations. They also addressed the
aim of detecting when the graft and the donors both retained the genetic alteration . Moreover, DNMT3A
[26]
R882 was engrafted in all cases while DNMT3A non-R882 was not. Furthermore, DNMT3A R882-positive
cases expanded more rapidly in the donors over DNMT3A non-R882 cases . Both increased HSC fitness
[26]
related to enhanced clonal cells and decreased normal cells due to HSC attrition led to a boosted fraction of
[15]
clonal cells .
Moreover, a context-dependent increase in HSC fitness related to cell-extrinsic stress and genotoxic stress
also plays a significant role . Some mutations under homeostasis can be relatively neutral but confer
[27]
increased HSC fitness under certain stressors. One of the most detrimental stressors for hematopoiesis is
genotoxic stress, representing a model for understanding the consequences of cytotoxic chemotherapy and
radiation . Bolton et al. described that DNMT3A mutation is often detected, but they also observed a
[27]
[27]
relative expansion of the clone carrying mutations in DNA-damage response genes such as PPM1D, TP53,
and CHEK2. These mutations were more frequently associated with clonal expansion even in a
multivariable logistic model adjusting for age, sex, race, and smoking . The authors uncovered the
[27]
radioisotope-based regimen and external-beam radiation to be highly associated with the presence of clonal
hematopoiesis as well as cytotoxic chemotherapy, while target therapy and immunotherapy were not;
among the types of cytotoxic chemotherapy, topoisomerase inhibitors or platin-derived compounds were
associated with increased risk of clonal hematopoiesis .
[27]

To better understand the effect of cell-extrinsic stress and infer these mechanisms, the TP53-dependent
genotoxic stress related to chemotherapy represents an archetypic example to precisely define if the mutated
[28]
[28]
clone is preexistent or consequential to cytotoxic agent exposure . Wong et al. reported that TP53-
mutated clones are present before chemotherapy is administered, and, during chemotherapy, this clone can
[29]
expand, acquiring additional mutations, evolving in a therapy-related myeloid neoplasm. McNerney et al.
substantially reviewed these findings by providing a model in which healthy individuals carry TP53
mutations that are generally neutral, but, after radiation or chemotherapy, novel mutations drive the
transformation into myeloid malignancies.

The immune attack represents the other example of cell-extrinsic stress, particularly T-cell mediated attack
is implicated in the pathophysiology of aplastic anemia and paroxysmal nocturnal hemoglobinuria . In
[30]
these cases, BCOR, BCORL1, and PIGA mutations are likely neutral under homeostasis, but the cells with
these alterations can evade the cytotoxic effect of T lymphocytes and expand, particularly after
immunosuppressive treatment . The role of DNMT3A and ASXL1 in immune evasion is much less
[31]
elucidated, despite subjects affected by these mutations being at high risk of progression to myelodysplastic
syndrome (MDS) and AML . However, their primary role seems to be played in inflammation and aging.
[31]
Clonal hematopoiesis, aging, and inflammation
An increased prevalence of somatic mutations according to age, mainly involving DNMT3A, TET2, and
ASXL1, ensues from dissecting CHIP- and age-related clonal hematopoiesis; moreover, CHIP is associated
with a greater risk for inflammatory co-morbidities (i.e., type II diabetes, atherosclerosis, or stroke) [20,21]
[Figure 1].