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Potential mechanism found for high TP53 mutation incidence in therapy-related AML, myelodysplastic disorder
NEW ORLEANS — Hematopoietic stem cells that acquire heterozygous TP53 mutations as a function of normal aging may be chosen in the presence of cytotoxic therapy in patients with therapy-related-acute myeloid leukemia and therapy-related-myelodysplastic syndrome, according to research presented at the ASH Annual Meeting and Exposition.
“The traditional viewpoint has been that cytotoxic therapy directly induces the mutational damage resulting in acute myeloid leukemia and myelodysplastic syndrome,” Terrence N. Wong, MD, PhD, of the department of medicine in the divisions of hematology and oncology at Washington University School of Medicine in St. Louis, told HemOnc Today. “We believe our data suggest that this is not the case, at least for a significant fraction of the cases, particularly the TP53-mutated ones. We know that individuals have a genetically heterogeneous hematopoietic stem cell population, and our data suggest that cytotoxic therapy is selecting for the chemo-resistant ones. We believe that this explains many of the features of therapy-related-acute myeloid leukemia and therapy-related-myelodysplastic syndrome, particularly why these disease our treatment-resistant.”
The study included 111 patients, of whom 52 had therapy-related-acute myeloid leukemia and 59 had therapy-related-myelodysplastic syndrome.
TP53 mutations were most frequent (33.3%); TP53 was the only gene mutated at a higher frequency in both populations studied vs. de novo acute myeloid leukemia or myelodysplastic syndrome.
Researchers hypothesized that hematopoietic stem cell clones that harbor aging-relatedTP53 mutations are present in a subset of healthy patients. To test this hypothesis, they developed a next generation sequencing technique that detects rare subclones harboring TP53 mutations to as low as 1 in every 1,000 cells.
Six cases of therapy-related-acute myeloid leukemia and therapy-related-myelodysplastic syndrome had specific TP53 mutations in which blood or bone marrow were gathered between 3 years and 8 years before the development of therapy-related-acute myeloid leukemia and therapy-related-myelodysplastic syndrome.
One patient had bi-allelic mutation of TP53 identified in mobilized peripheral blood leukocytes 6 years before the development of therapy-related-acute myeloid leukemia at a frequency of 0.5%.
Next, researchers set out to test the hypothesis thatTP53 mutations confer a clonal advantage after chemotherapy. Mixed bone marrow chimeras containing wild type and Tp53+/- cells were generated. The researchers observed no clonal advantage of Tp53+/- cells in untreated chimeras. Yet, significant growth in Tp53+/- hematopoietic stem cells were observed when treated with N-ethyl-N-nitrosourea.
“This further reinforces that our hematopoietic stem cell population is not a single clonal population, but a heterogenous population,” Wong said. “Clinically, this gives a potential mechanism for how certain treatments can influence this population and potentially could help rationally guide treatment regimens to lower the risk of therapy-related-acute myeloid leukemia and therapy-related-myelodysplastic syndrome.”
For more information:
Wong TN. Abstract #5. Presented at: ASH Annual Meeting and Exhibition; Dec. 7-10, 2013; New Orleans.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Acute myeloid leukemia can occur after radiation or chemotherapy for other malignancies. Such secondary AMLs (sAML) are especially troubling, as they occur in patients who are likely cured of their original cancer and have assumed a normal life.
These sAML also are extraordinarily difficult to treat, rapidly acquiring resistance to all conventional therapy. Thus, to be caught once again by malignancy — and a malignancy that is most often incurable — when the patient thought they had escaped and survived is a horrific problem for these patients.
SAML often originate from the hematopoietic stem cell (HSC), one reason why they are so difficult to treat. Wong and colleagues have provided novel and unpredicted insight into how sAML develop. Most of us have always assumed, reasonably, that the DNA damage from the prior chemotherapy or radiation generated mutations in oncogenes and tumor suppressor genes, such as TP53, that resulted in sAML. This hypothesis leads to two predictions: 1) the mutational burden is higher in sAML than de novo AML, and 2) the spectrum of mutations would be far wider than de novo AML.
Sequencing paired skin and leukemia samples, Wong and colleagues found that neither of these predictions were true. The same mutations were found with the same frequency in both types of AML. This led them to an alternate hypothesis: Mutations in tumor suppressors such as TP53 were already present at the time of therapy, and the therapy selected for HSC with such mutations, because they would have a competitive advantage for proliferation.
Wong and colleagues found in several cases that this hypothesis was true. There were indeed TP53 point mutations present in marrow samples prior to the high-dose therapy (eg, preparative regimen for stem cell transplantation) that would have been thought to generate the sAML. These early acquisitions of TP53 mutations led to the genomic instability seen later in the sAML, and can mediate the resistance to treatment seen in most sAML.
These data have several remarkable consequences. First, even low-dose radiation or chemotherapy can damage HSC and put them at risk for sAML. HSC TP53 mutations can occur after standard treatment for many types of cancers. This means that there may be a rising risk of sAML as our cancer survivor population ages.
Second, it might be possible to predict who is at risk for sAML by sequencing blood leukocytes for TP53 mutations. If one could predict who is likely to develop leukemogenic genomic instability, then one could at least increase monitoring.
Finally, we recently found that PARP1 is essential for chromosomal translocations to occur, and that the clinically relevant PARP1 inhibitors could almost completely abrogate these translocations (Wray J. Blood. 2013;121:4359-4365). Because a percentage of sAML result from translocations, such as in the MLL gene, this raises the extraordinary possibility that those patients at high risk for sAML — identified by TP53 point mutations — could be treated with PARP1 inhibitors to prevent the occurrence of sAML.