Tackling sub-cellular storage units called P-bodies could lead to new treatments for acute myeloid leukaemia (AML), according to the findings of an international research project.
P-bodies are storage reservoirs within cells for messenger RNA (mRNA) molecules and other proteins. The researchers found that AML cells carry elevated numbers of P-bodies compared to normal blood stem cells. Their effect is to sequester mRNA that might suppress the growth of the AML cells, according to the findings reported in Nature Cell Biology.
The researchers suggest ways in which therapies might target the P-bodies in AML cells and release the cancer fighting mRNA. Initial studies suggest this has little impact on healthy cells, they say.
Scientists at Baylor College of Medicine, Texas, USA, at the University of Veterinary Medicine in Austria and the Josep Carreras Leukaemia Research Institute in Spain worked together on the project.
Researcher Dr Bruno Di Stefano, of Baylor College of Medicine, said: “Our first insight into how leukaemia cells might derail normal translation control was the discovery that they harboured more P-bodies than their normal counterparts.
“Excitingly, P-bodies were essential for the growth of leukaemia cells, but not normal blood cells, suggesting a potential AML-specific dependency.”
He added: “We discovered that leukaemia cells sequester mRNAs encoding tumour suppressor proteins within P-bodies. Of particular importance, these mRNAs were not degraded, and by forcibly dissolving P-bodies, we found that the mRNAs could be translated into proteins capable of curtailing AML.”
Researcher Dr José Sardina, of the Josep Carreras Leukaemia Research Institute, said: “Abolishing P-bodies by removing DDX6, one of the proteins responsible for their formation, triggered the death of cancer cells in diverse models of human AML, across multiple different subtypes and mutations. AML is a heterogeneous disease and finding a molecular pathway that might be a conserved Achilles’ heel is quite 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.”
Source:
Kodali S, Proietti L, Valcarcel G, López-Rubio AV, Pessina P, Eder T, Shi J, Jen A, Lupión-Garcia N, Starner AC, Bartels MD, Cui Y, Sands CM, Planas-Riverola A, Martínez A, Velasco-Hernandez T, Tomás-Daza L, Alber B, Manhart G, Mayer IM, Kollmann K, Fatica A, Menendez P, Shishkova E, Rau RE, Javierre BM, Coon J, Chen Q, Van Nostrand EL, Sardina JL, Grebien F, Di Stefano B. (2024) “RNA sequestration in P-bodies sustains myeloid leukemia.” Nature Cell Biology, 21 August 2024, doi: 10.1038/s41556-024-01489-6.
Link: https://www.nature.com/articles/s41556-024-01489-6
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