Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential

Abstract

Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.

Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

“…This is largely driven by a shared 110 association with age. However, recent studies further propose a link between prior exposure to oncologic therapy and CH 7, 11 .…”

Patterns of mutations in TP53 mutated AML

“…Thus, the TP53 mutations appear to provide a selective advantage in the associated hematopoietic stem/progenitor clones, which facilitates subsequent outgrowth and expansion during this evolutionary bottleneck. Subsequent studies have evaluated a broader series of patients with CHIP and compared subjects who had been previously exposed to chemotherapy or had not had prior chemotherapy treatment [30, 31]. In these studies, variants in TP53 and in PPM1D were strongly enriched in the patients with prior chemotherapy exposure.…”

Dynamic Clonal Hematopoiesis and Functional T-cell Immunity in a Super-centenarian

“…We have identified and validated 308 unique somatic mutations in the blood from an exceptionally old, but apparently healthy individual at age 110. Identified somatic mutations included a splice-donor mutation in intron 11 of DNMT3A (NM_022552.4, chr2:25,469,028 C>T, c.1429+1 G>A), a somatic mutation that has recurrently been reported in patients with hematopoietic or lymphoid malignancies (COSM5945645) [Shin 2016, Wong 2018, Zehir 2017]. A clinical examination of peripheral blood, however, revealed neither cytopenias nor dysplastic morphologies ( Supplemental Material ).…”