Memoli, Mara (2022) Composition and clonal evolution of TP53 mutated acute myeloid leukemia. [Tesi di dottorato]

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Abstract

Acute myeloid leukemias (AMLs) result from the consecutive acquisition of different genetic lesions. AMLs mutated for TP53 tumor suppressor gene have been largely demonstrated to be associated with both a complex karyotype and a poor prognosis. Our study has focused on the investigation of the clonal architecture of TP53-mutated AMLs, by differentiating between de novo AMLs, induced AMLs (t-AMLs) and secondary AMLs (s-AMLs) consecutive to a myeloproliferative neoplasm (MPN), by both a standard sequencing and genotypic analysis of progenitor-derived colonies. We observed several patterns of clonal architecture, which suggest that the amplification of the TP53-mutated clone as enabled by chemotherapy for t-AML, as well as by the acquisition of mutations in epigenetic regulators, such as DNMT3A or TET2, for de novo AML. The s-AMLs following MPN may present a profile similar to that of t-AMLs, with mostly isolated TP53 mutations, though also to that of de novo AMLs. Assuming that the high frequency of TP53 mutations in s-AMLs may be due to selection of mutated cells due to treatment, we tried to identify small TP53-mutated clones in a series of MPN by high-sensitivity error corrected sequencing (NGS-HS), distinguishing between patients either treated or not with Hydroxyurea (HU). We observed several mutated clones in both treated (5/12) and untreated (2/5) patients. However, such data need further confirmation on larger sample sizes, as well as by the confirmation of the variants by digital PCR. We further applied NGS HS method to characterize the molecular profile of sickle cell disease (SCD) patients, to detect the presence of TP53 subclones, potentially susceptible to clonal expansion following treatment with HU, with consequent onset of myeloid neoplasms. In conclusion, TP53-mutated AMLs follow several patterns of clonal architecture, where the expansion of TP53-mutated clones seems to require a second event, i.e. either treatment or mutation of an epigenetic regulator involved in age-related clonal hematopoiesis (ARCH). For s-AML patients we observed that the duration of exposure to HU is positively associated with the presence of mutated TP53 clones (p<0.001).Therefore, a complete molecular characterization by NGS, could be useful to detect and to monitoring the presence of TP53 subclones in both MPN and SCD patients. Our hypothesis need to be confirmed by specific in vivo study.

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