Abstract
SummaryClonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions.Video
Highlights
One of the most serious risks of cytotoxic chemotherapies for cancer is the development of secondary, hematopoietic malignancies some years in the future
PPM1D Mutations Are Relatively Common in TherapyRelated AML and MDS We performed targeted-capture sequencing of 295 cancer genes combined with amplicon sequencing on diagnostic bone marrow samples from 156 patients with therapyrelated myelodysplastic syndrome (t-MDS) (n = 79) or therapy-related acute myeloid leukemia (t-AML) (n = 77)
PPM1D mutations were found in 20% of these cases (31/156) and at similar frequencies in both groups (t-AML: 15/77, 19.5%; t-MDS 16/79, 20.2%)
Summary
One of the most serious risks of cytotoxic chemotherapies for cancer is the development of secondary, hematopoietic malignancies some years in the future. Chemotherapy and radiation might directly inflict the DNA damage that, when inappropriately repaired, produces the subsequent cancer-driving mutation It is possible, that cancer therapies might exert selective pressures on hematopoietic stem cells (HSCs) such that certain mutant populations (known as clones) have a selective advantage under cytotoxic conditions. If the mutant clones survive longer, they may accumulate more mutations with time This could be why the expansion of mutant clones, known as clonal hematopoiesis (CH), is associated with an increased risk of developing hematologic malignancies (Genovese et al, 2014; Jaiswal et al, 2014; Xie et al, 2014): certain mutant clones could serve as premalignant cells with some sort of growth advantage, which acquire cancerdriving mutations. The nature of the association between CH and malignancy is not clear
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