Preexisting TP53 mutation in therapy-related acute myeloid leukemia
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KeywordsTherapy-related myeloid neoplasms TP53 Leukemogenesis
Therapy-related myeloid neoplasms (t-MNs) are a unique clinical entity occurring as late complication of chemotherapy and radiotherapy administered for a primary disease . According to the WHO classification, t-MNs are thought to be due to mutational events in hematopoietic stem and precursor cells (HSPCs) induced by these treatments . However, no consistent biomarker has been identified yet that classifies a particular neoplasm as “therapy-related” . This raises the possibility that other mechanisms may also be operational in their pathogenesis. We and others , therefore, hypothesized that mutations contributing to leukemic transformation were preexisting in HSPCs of some of these individuals.
We established a highly sensitive PCR assay specific for this rearrangement (Fig. 1b) and could unambiguously demonstrate the presence of the TP53 mutation in the patient’s BM obtained at the time of the lymphoma staging (Fig. 1c). Surprisingly, the TP53 duplication was also detected in a reactive lymphadenitis sample obtained 7 years before lymphoma diagnosis (Fig. 1c). To further demonstrate that expansion of the TP53 mutated clone occurred following cytotoxic treatment, we quantified the TP53 duplication by digital PCR (dPCR) which showed that the relative proportion of mutated cells increased substantially in the t-AML specimen (Fig. 1d). It, furthermore, confirmed the TP53 duplication being a somatically acquired event as it was absent from a skin biopsy obtained at the time of the leukemia diagnosis.
In the case report presented here, we were able to demonstrate that cytotoxic treatment did not induce a leukemia-specific mutation but rather may have facilitated the expansion of a pre-leukemic clone harboring a somatic TP53 mutation. Since dPCR data quantifying the TP53 duplication were comparable in lymph node and pretreatment BM, the mutation might have occurred in HSPCs that retained their lymphoid as well as myeloid differentiation potential and remained dormant for many years. This finding challenges current concepts of therapy-related leukemogenesis and is in line with data presented at the 2013 annual meeting of the American Society of Hematology . There, somatic TP53 variants could be identified at low frequencies in mobilized peripheral blood leukocytes of two t-MDS/t-AML cases years before diagnosis. However, in clinical practice, HSPC harvests from peripheral blood are performed following intense chemotherapy including application of recombinant granulocyte-colony factor. Here, we provided definitive evidence that a leukemia-specific mutation could be found in HSPCs before any cytotoxic treatment was administered.
The work was funded in part by the Austrian National Bank, Anniversary Fund (grant no. 13918), Land Steiermark, Leukämiehilfe Steiermark and “Vereinigung Forschungsförderung” at Medical University of Graz, Austria. E.S. is supported by a dissertational grant from the Austrian Society of Hematology and Oncology.
Ethical standards statement
The study was approved by the ethics committee of the Medical University of Graz, Austria, and written informed consent was obtained from all patients.
E.S., K.K., E.H., M.R.S., G.H. and H.S. conceived experiments. K.M. and E.S. performed Sanger sequencing. K.K. performed and analyzed targeted deep sequencing. E.H. performed and analyzed dPCR. G.H. and H.S. provided patient samples. E.S. and H.S. had full access to all of the data in the study and take responsibility for their integrity and the accuracy of the data analysis. E.S. and H.S. wrote the manuscript which was approved by all authors.
Conflict of interest
The authors declare no competing financial interests.
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