Some Degenerated Blood Cells’ DNA Reveals Therapy-Specific Mutation Patterns

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Chemotherapeutic drugs kill tumor cells and kill healthy cells, which may lead to leukemia, for example. Using platinum-containing chemotherapeutics has been discovered by scientists to induce blood cell mutations in the usual way. Other chemotherapeutic drugs lacked these signs, although there was a strong correlation between treatment duration and therapy-specific alterations in subsequent metastases.

Chemotherapy medicines that damage tumor cells' DNA affect cell division as a side effect. Chemotherapy has a more significant impact on quickly developing tumor cells than healthy body cells. However, even these may be harmed due to the occurrence of mutations.

Leukemia may emerge years later as long as blood stem cells in the bone marrow are damaged during chemotherapy. Unchecked degeneration and proliferation of immature blood neural stem cells occur.

Researchers from the Barcelona Institute of Science and Technology in Spain write, "Until now it was unclear whether drug-related mutations specifically caused the cases of leukemia after chemotherapy or whether they are a consequence of the evolutionary bottleneck that chemotherapies represent for blood formation, or whether both factors interact.".

In cancer cells, scientists have already found evidence that some chemotherapeutic drugs leave behind DNA mutation patterns that serve as a visual cue to the drug's presence. "As a result, we have assumed that detecting the mutation footprint of chemotherapy treatments is a valuable technique for studying their impact on such illnesses, even in therapy-related leukemia," the researchers said.

The Aftereffects of Platinum-Based Chemotherapy

A team led by Pich studied the gene sequences of 30 patients with therapy-related leukemia, and 32 others who had leukemia formed spontaneously without any previous treatment. For example, cisplatin, oxaliplatin, or carboplatin were used in eight of the patients with therapy-related leukemia who had previously undergone platinum-based chemotherapy. Toxic blood cells left a genetic imprint on all of them, according to researchers.

However, patients who received other chemotherapy drugs like 5-fluorouracil did not have this mutation pattern in their blood cells, even though these drugs are also linked to the occurrence of leukemia tumors.

One of the reasons for this is that these drugs all have distinct mechanisms of action: While platinum-based chemotherapies directly damage the DNA of cells, 5-fluorouracils only alter the DNA building blocks that cells require for the production of new copies of the genetic material. Only when the cancer cells proliferate and absorb the changed nucleotides are they harmed.

The duration may also be critical.

In addition, another element comes into play, as Pich and his colleagues discovered in follow-up research involving more than 700 cancer patients. These patients' primary tumors were treated with platinum-based agents or 5-fluorouracil, but they eventually developed metastases. The researchers also looked at the cancer cells' genomes and therapy-specific mutation patterns in these test participants.

The more extended chemotherapy was halted following 5-fluorouracil treatment, the more probable it was that cancer cells with therapy-specific alterations would reappear. When it came to platinum-based agents, this was not the case. Another reasoning is this: "These mutations induced by 5FU only arise if the pool of DNA building blocks was not replenished during cell division," stated Pich and his colleagues." 5-fluorouracil exposure in cells increases with time, which means it's more probable.

What do clones of blood cell lines reveal?

The researchers also studied clonal hematopoiesis. Mutations in blood stem cells cause-specific stem cells to increase more than others, resulting in many clones. In some people, they may be harmful, while in others, they encourage cancer and other illnesses like leukemia. It's possible to determine if clonal hematopoiesis started before chemotherapy, he claims, thanks to Pich's research.

Because of this, although clonal expansions that produced leukemia did not occur until after chemotherapy and were likely induced by the medicines, blood cell clones that generated clonal hematopoiesis existed before treatment. Because of their mutations, they could forgo chemotherapy, which allowed them to grow and develop at a faster rate. As the group says, a backlog was to blame.

This study "demonstrates the utility of particular mutation signatures, such as those linked with chemotherapy exposure," said the researchers. "Our research provides a method to investigate some of the longer-term consequences of exposure to such cytotoxic therapies in cancer survivors."


The evolution of hematopoietic cells under cancer therapy Published in Nature Communication

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