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New evidence shows that in Acute Myeloid Leukaemia cells, RNA molecules from tumour suppressor genes are hijacked by the cell’s RNA processing centres, the P-bodies, effectively silencing its antitumour effects. The evidence, presented at the prestigious journal Nature Cell Biology by an international team of researchers, offers a new perspective to better understand malignant transformation in Acute Myeloid Leukaemia cells. Members of the Epigenetic Control of Haematopoiesis group at the Josep Carreras Leukaemia Research Institute, headed by Dr. José Luis Sardina, co-led the research.
Acute Myeloid Leukaemia (AML) is a highly aggressive blood cancer usually found in adults, accounting for 1 out of every 3 diagnosed leukaemia cases. AML originates in the bone marrow, where altered haematopoietic progenitor cells fail to differentiate properly and proliferate without control. The genetic complexity of AML makes it difficult to treat and, despite the important advances seen lately in cancer research, its overall 5-year survival is still around 30 %.
To solve the low survival issue in AML, a deeper understanding of what happens within an AML cell is needed. New knowledge might help find potentially druggable targets and pave the way for developing new therapies. With this purpose, a team of researchers led by Dr. Bruno Di Stefano (Stem Cells and Regenerative Medicine Center (STaR) and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, USA), along with Dr. Florian Grebien (St. Anna Children’s Cancer Research Institute and University of Veterinary Medicine Vienna, Austria) and Dr. Jose Luis Sardina (Josep Carreras Leukaemia Research Institute, Spain) focused on the post-transcriptional aspects of AML gene expression, known to be dysregulated in cancer cells.
In a nutshell, gene expression refers to all the actions an active gene takes to make its information matter. This usually means making an RNA copy of its actual information (transcription) and then synthetising proteins from it (translation). Cells have various mechanisms to control gene expression to ensure its performance, including post-transcriptional regulation. Alterations in these mechanisms can lead to oncogenic transformation.
The international team found that AML cells had an unusually high number of P-bodies, cellular structures related to RNA processing, a key step of gene expression. When getting a closer look, they discovered that RNAs from tumour suppressor genes, those preventing the oncogenic transformation of the cell, were piling up in there, not being translated and, thus, not being able to produce its proteins and guide the fate of the cell.
Although the mechanism causing the preferential hijacking of mRNA encoding tumour suppressors into the p-bodies remains to be fully elucidated, the evidence is solid. Notably, when researchers forced the dissolution of the P-bodies, the cells resumed their anti-cancer programmes. As a result, the genome underwent a rewiring process, healthy gene expression patterns were re-established, and the cells exhibited a much more manageable behavior: either undergoing cell death or transitioning to a non-proliferative state.
Deepening into the P-body hijacking mechanism, the team found several proteins involved in forming these intriguing cellular entities, especially DDX6. Indeed, depleting this protein, both in vitro and in vivo, in AML animal models and in human xenograft AML models effectively destabilized P-body formation, freeing the stuck RNAs with little or no effect on healthy progenitor cells.
Dr. José L. Sardina, principal investigator at Josep Carreras Institute and co-corresponding author of the study, considers that these results are a very important step in Acute Myeloid Leukaemia research: «AML is a heterogeneous disease and, therefore, finding a molecular pathway that might be a conserved Achilles’ heel across multiple subtypes and mutations is very exciting. Of equal importance, P-body loss had little effect upon normal blood cell production, further highlighting the potential of targeting P-body formation in AML».
With these results, the researchers not only understand the inner mechanisms leading to oncogenic transformation in AML much better but are also optimistic about the potential of new therapies targeting P-bodies in AML and, perhaps, in other malignancies in the future.
This study has been published in Nature Cell Biology and had the valuable participation of 2 additional research groups from the Josep Carreras Institute: Dr. Biola M. Javierre’s and Dr. Pablo Menéndez’s. The research performed at Dr. José L. Sardina’s laboratory has been funded by Worldwide Cancer Research, Spanish Ministry of Science, Innovation and Universities – State Research Agency, Instituto de Salud Carlos III and CERCA (Generalitat de Catalunya).
