These researchers from the Baylor College of Medicine identify a gene with a beneficial role, especially in the case of chemotherapy: PPM1D, which gives a winning boost to stem cells after chemotherapy. Data documented in the journal Cell Stem Cell which constitute a first step towards the development of therapeutic approaches aimed at “hyperactivating” PPM1D signaling.
Chemotherapy is associated with an increased risk of leukemia years after treatment, but the cause of this association remains poorly understood. The team led by researchers from Baylor College of Medicine and MD Anderson Cancer Center (Houston) combined different clinical and experimental studies and found that the gene called PPM1D frequently mutates in patients receiving chemotherapy and that this mutation promotes the development of leukemia years later. The study suggests that the presence of this mutation and other mutations should be considered when choosing chemotherapy.
The researchers had previously discovered that PPM1D mutations were frequently present in the blood of leukemia patients years after receiving chemotherapy, so they wondered how PPM1D mutant cells could become dominant over their normal counterparts in the blood. bone marrow. Was this dominance due to superior expression or better survivability under adverse conditions? The researchers have thus become experts on the PPM1D gene, they have been studying it for more than 20 years.
Chemotherapy promotes the survival of cells with mutated PPM1D:these laboratory experiments which consisted of mixing cells with normal PPM1D and mutant PPM1D and then exposing them to different environmental conditions show that under normal conditions, cells with PPM1D mutation and normal cells grow at the same speeds. This suggests that mutated cells are not inherently stronger. However, after exposure to the drug cisplatin and other chemotherapy drugs, researchers observe that cells with the mutation dramatically outperform normal cells. Their results suggest that chemotherapy acts as a pressure on evolutionary selection that will promote the survival of cells with mutated PPM1D, because "they 'benefit' from this specific type of stress", explains Joanne Hsu, student at Baylor's medical and scientific training program: “So when a patient receives cisplatin-based chemotherapy, stem cells with PPM1D mutations survive better. This growth advantage could provide fertile ground for the subsequent acquisition of mutations that eventually lead to the development of secondary leukemia years later.”
Multiple clinical implications for the future: indeed, knowing that certain chemotherapeutic drugs can influence the risk of leukemia years later will help doctors make better and more personalized treatment choices.
Finally, non-mutated PPM1D appears here as a promising therapeutic target in patients, post-chemo and/or suffering from secondary leukemia.
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