• An IDIBELL study shows that increasing the methylation of a histone reduces the proliferation capacity of leukaemia cells in preclinical models and in patient samples.

Acute myeloid leukaemia (AML) is a blood cancer that occurs when certain cells in the bone marrow acquire alterations that cause them to proliferate uncontrollably. The risk of developing it increases with age, partly because the haematopoietic stem cells, responsible for generating the different blood cells, accumulate genetic and epigenetic changes throughout life —the latter consisting of chemical modifications of nucleotides or associated histone proteins—.

Now, a study led by the Bellvitge Biomedical Research Institute (IDIBELL) has identified an epigenetic modification that could contribute to the development of leukaemia and, at the same time, represent a possible therapeutic target. Specifically, the results show that increasing the methylation of histone H3 in lysine 9 (H3K9) reduces the proliferative capacity of leukaemia cells.

The work has been led by Dr. M. Carolina Florian, researcher and group leader in the Regenerative Medicine program at IDIBELL, and ICREA professor, in collaboration with Dr. Montserrat Arnan, researcher in the Hematopoietic and Lymphoid Tumors group at IDIBELL and head of the Myeloid Disease Unit at the Catalan Institute of Oncology (ICO). The study has been published recently in the journal Cancers.

Ageing and epigenetics

Hematopoietic stem cells accumulate modifications throughout life that can alter their functioning and promote the onset of diseases. Among these modifications are epigenetic changes, which regulate the activity of genes without modifying the DNA sequence.

In previous studies, Florian’s team had observed that a decrease in H3K9 methylation in hematopoietic stem cells causes characteristics associated with premature aging. In the new study, the researchers found that this alteration is also associated with a pre-leukemic state, that means, cellular characteristics that can promote the development of leukaemia.

In addition, leukemia cells have low levels of H3K9 methylation and the experimental data obtained by this study indicate that maintaining these levels is important for cells to continue proliferating.

Increasing methylation slows down leukemia cells

To test whether this characteristic could become a vulnerability of leukemic cells, the researchers used IOX1, a compound that increases H3K9 methylation levels. The treatment reduced the proliferation capacity of leukemic cells and decreased the activity of genes related to proliferation and leukemic potential.

The effect was observed in different experimental models, including cell lines, mouse models and samples donated by ICO-IDIBELL patients with AML. The results also suggest that this vulnerability could be maintained regardless of age, the proliferative status of leukemia cells and their genetic characteristics.

Overall, the study identifies H3K9 methylation as a possible therapeutic target for acute myeloid leukaemia and opens a new line of research based on the modulation of the epigenetics of leukaemic cells. These are still preclinical results, and further studies will be needed to determine whether this strategy can be applied therapeutically in patients.