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Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.” 
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”