In Therapy-Related AML, p53 Mutations Already Exist

Mutations in the tumor suppressor p53 are thought to arise in hematopoietic stem cells after exposure to chemotherapy and radiotherapy, causing therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), a cancer of the blood and bone marrow.

But in a surprising new finding that reverses this hypothesis, researchers now provide evidence that therapy-related AML actually arises due to the selection of pre-existing hematopoietic stem cells that harbor p53 mutations. Hematopoietic stem cells may acquire deleterious p53 mutations as a result of the normal aging process and are likely selected in the context of cytotoxic therapies, such as chemotherapy and radiation therapy.

The study results were presented at the plenary session of the 2013 American Society of Hematology (ASH) Annual Meeting and Exposition, held in New Orleans.

“This new model explains many of the clinical features observed in therapy-induced AML,” said study presenter Terrence Neal Wong, MD, PhD, of Washington University in St. Louis, during his presentation. “This early loss of p53 may provide a mechanism for the resistance to chemotherapy and poor survival in these patients.”

AML is an aggressive malignancy of the bone marrow, characterized by a high relapse rate and resistance to chemotherapy agents, particularly for therapy-related AML. “Therapy-related myeloid malignancies are among the most feared long-term consequences of exposure to chemotherapy or radiation,” said Benjamin L. Ebert, MD, PhD, of the Brigham and Women’s Hospital and Harvard Medical School in Boston, who introduced the plenary presentation.

Therapy-related AML generally develops months or years after exposure to either radiation or chemotherapy. This type of blood disorder is characterized by a high incidence of p53 mutations compared with de novo AML, as well as a complex karyotype and poor overall survival.

The long-standing theory for the development of therapy-related AML is that the accumulation of mutations, including in key driver genes, as a result of exposure to cytotoxic therapy ultimately leads to clonal expansion and AML. But one observation was not consistent with this theory: Therapy-related AML does not have a particularly high mutation burden compared with de novo AML, which would be expected as a result of exposure to chemotherapy or radiotherapy.

Wong showed evidence that p53 mutations are present in the existing pool of hematopoietic stem cells prior to cytotoxic therapy exposure. This population of cells has a selective advantage and expands following therapy and acquires somatic mutations and karyotypic complexities that can ultimately lead to therapy-related AML.

Wong and colleagues expanded their initial analysis of 22 therapy-related AML and 49 de novo AML cases to include an additional 89 patients with therapy-related AML or MDS, finding that p53 mutations occurred in 31.5% of cases and was the only mutation that occurred at a higher frequency compared with de novo AML or MDS.

The study authors used next-generation whole genome sequencing that is able to detect rare cell subclones on paired bone marrow and skin specimens from therapy-related AML patients at diagnosis. They were able to show several cases where the driver p53 mutation was present prior to the emergence of other somatic driver mutations and other cytogenic abnormalities, and treatment exposure.

Using bone marrow chimeras, Wong showed that the heterozygous loss of p53 results in a competitive advantage following chemotherapy but not if the cells are not exposed to cytotoxic therapy. An early acquisition of a p53 mutation in a founding hematopoietic stem cell clone likely contributes to later AML development following cytotoxic therapy.

Mutations of p53 are particularly common in therapy-related diseases, including hematopoietic cancers. The gene plays a key role in response to cytotoxic-based therapies and an essential role in maintaining genomic stability.

This study result could help identify patients at high risk for therapy-related AML by monitoring patients and identifying hematopoietic stem cells with existing p53 mutations prior to cytotoxic therapy, said Ebert during his presentation. Additionally, those patients who have received cytotoxic therapy could be monitored for p53-mutated clones.