Figure 4.

Selective pressures may shape clonal expansion of mutant HSCs. During aging HSCs lose their self-renewal capacity as the cells continuously replenish the blood system. As a result, HSCs with mutations that skew towards self-renewal, such as Tet2 or DNMT3A, will have a selective advantage over aged HSCs [84,86]. However, in a person that previously received chemotherapy, HSC clones with different mutations will arise. Chemotherapy induces DNA damage in HSCs and activates DNA damage repair pathways or apoptosis. The incidence of HSCs with mutations in DNA damage repair pathways such as TP53 or PPM1D is significantly higher in people with previous chemotherapy treatment [66]. Specific pressures may allow for the expansion of less common mutations such as JAK2^V617F. MPN patients with JAK2^V617F mutations have elevated TNFα, contributing to the chronic inflammatory environment. Under chronic inflammation, normal HSCs will become exhausted and lose their competitive fitness, allowing for the emergence of mutant HSCs that are resistant to TNFα [85].