Acute myeloid leukaemia (AML) is an aggressive haematological malignancy characterized by uncontrolled and rapid proliferation of immature myeloid cells and their accumulation in the bone marrow. The incidence of AML increases with age and predominantly affects people over 60, although it can affect younger adults and children as well. Given the aggressive nature of the disease and its high mortality rate, AML remains a major unmet medical need and requires investigation from new perspectives to improve clinical outcomes. AML development is driven by both genetic and epigenetic alterations in haematopoietic progenitor or blast cells. During the course of past decade, increasing evidence has highlighted the pivotal role of epigenetic mechanisms in cancer pathogenesis, prompting growing interest in studying AML through this lens.
The focus of this research project is HEN methyltransferase 1 (HENMT1), which has been identified in the lab as a promising candidate for investigation. In silico analysis suggested that HENMT1 may be epigenetically regulated in cancer through DNA methylation. HENMT1 introduces specific modification (2’-O-methylation) to the 3’ end of small non-coding RNAs known as PIWI-interacting RNAs, simply piRNAs. This modification stabilizes piRNAs and enables their function within their small silencing pathway, keeping our genome safe primarily from transposable elements. Recent studies have increasingly linked piRNAs to cancer development and progression, raising our interest in understanding whether aberrant HENMT1 expression, one of the key factors in the piRNA biogenesis, may contribute to oncogenic processes by further altering downstream factors of this machinery.
We hypothesize that epigenetic regulation of HENMT1 in AML impacts piRNA metabolism, thereby influencing tumorogenic features of transformed cell. To investigate this, the project will pursue three main objectives: studying the methylation status of HENMT1 in the context of AML using cell lines and patients’ samples to validate in silico data (i), to investigate HENMT1 function using AML cellular models (ii), and to identify new potential therapeutic entry sites for AML related to HENMT1 function (iii).

Furthermore, collaboration with clinicians throughout the course of this project will provide additional insight into the complex biology of AML and facilitate the translational relevance of our findings. This interdisciplinary approach aims to contribute to the identification of novel therapeutic strategies addressing the unmet clinical needs in AML.

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