A small proportion of cancer patients who receive radiotherapy or chemotherapy can develop acute myeloid leukemia – an aggressive blood cancer with a poor prognosis. Now, a new study suggests this is because of a build-up of age-related gene mutations in blood cells that resist treatment and then multiply at an accelerated rate.

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Contrary to what many believe, the leukemia that sometimes follows cancer treatment may not be a result of chemo or radiotherapy but due to accumulated, age-related mutations in cells that resist therapy and then multiply rapidly.

The finding challenges the conventional idea that therapy-related acute myeloid leukemia (AML) is a direct result of the cancer treatment.

Chemotherapy and radiation therapy fight cancer by inflicting a barrage of gene changes that accumulate in the cancer cells, causing so much havoc that they die. Unfortunately, for a small proportion of patients, this is followed by therapy-related AML.

In the US, there are about 18,000 new cases of AML every year, including 2,000 that follow exposure to chemotherapy or radiation therapy. Even with aggressive treatment, therapy-related AML is almost always fatal.

Therapy-related AML typically develops 1-5 years after chemotherapy or radiation, and the rate at which it occurs depends on the cancer being treated. For instance, 10% of patients with lymphoma that recurs following chemotherapy develop therapy-related AML. But in the case of breast cancer, only 0.1% of patients develop therapy-related AML.

Now, in a new study published in the journal Nature, researchers at Washington University School of Medicine in St. Louis, MO, challenge the idea that it is the cancer treatment itself that causes therapy-related AML.

They suggest the findings will lead to new ways to research and predict which patients are at risk of developing therapy-related AML, and also to prevent it.

In their study, the researchers focus on a well-known cancer gene – P53. They find that mutations to this gene accumulate in blood stem cells as a person gets older, years before they are diagnosed with cancer.

P53 is a tumor suppressor gene – its normal function is to stop cells dividing uncontrollably and to maintain the integrity of chromosome structures inside cells. But when both copies of the gene are mutated, cancer can follow.

If and when a person with a build-up of P53 mutations in their blood stem cells develops cancer, and then has chemotherapy or radiotherapy, the mutated cells are more resistant to treatment and proliferate more quickly. It is this sequence of events that can lead to AML, the authors argue.

“This is contrary to what physicians and scientists have long accepted as fact,” says senior author Dr. Richard K. Wilson, director of The Genome Institute at Washington University.

In one part of the study, the team sequenced the genomes of 22 therapy-related AML cases and found the genetic mutations in the leukemia cells of those patients were similar in number and type as those found in AML patients who had not received chemotherapy or radiation therapy – suggesting the cancer treatment was not to blame.

In another part of the study, the researchers analyzed blood samples from 19 healthy people aged 68-89 years with no history of cancer or chemotherapy. To their surprise, they found nearly 50% of them had mutations in one copy of the P53 gene – suggesting these accumulate with age.

“Most of the time, these mutations are harmless because they only affect one copy of the gene,” says Dr. Wilson.

These two findings caused the team to dig further. What was happening earlier in people’s lives? What is the exact P53 mutation that causes therapy-related AML years later?

Blood stem cells are made in bone marrow. So, the researchers sourced and analyzed bone marrow samples from seven patients with therapy-related AML whose samples had been collected and stored before they developed the blood cancer between 3 and 6 years later.

In four of the seven samples, the team found very low levels of specific P53 mutations. It is possible that these P53 mutations were present in the other three samples, but at levels too low to detect, say the researchers.

However, another possibility is that other age-related mutations may have played a role in triggering therapy-related AML, they note. The team is already conducting follow-up studies to look for other age-related mutations.

And finally, using mice, the researchers showed chemotherapy causes blood stem cells with P53 mutations to divide more quickly – but this did not happen in blood stem cells without P53 mutations.

In September of this year, Medical News Today learned of another study where researchers uncovered a genetic network that fuels AML and its precursor disease – myelodysplastic syndrome – paving the way for new treatment strategies.