Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

Autor:	Woodley, Keith, Dillingh, Laura S, Giotopoulos, George, Madrigal, Pedro, Rattigan, Kevin M, Philippe, Céline, Dembitz, Vilma, Magee, Aoife MS, Asby, Ryan, Van De Lagemaat, Louie N, Mapperley, Christopher, James, Sophie C, Prehn, Jochen HM, Tzelepis, Konstantinos, Rouault-Pierre, Kevin, Vassiliou, George S, Kranc, Kamil R, Helgason, G Vignir, Huntly, Brian JP, Gallipoli, Paolo
Přispěvatelé:	Giotopoulos, George [0000-0003-1390-6592], Madrigal, Pedro [0000-0003-1959-8199], Philippe, Céline [0000-0002-8546-3893], Dembitz, Vilma [0000-0002-9463-253X], van de Lagemaat, Louie N [0000-0002-2947-1557], Mapperley, Christopher [0000-0002-2059-7006], Tzelepis, Konstantinos [0000-0002-4865-7648], Rouault-Pierre, Kevin [0000-0001-7671-7364], Vassiliou, George S [0000-0003-4337-8022], Kranc, Kamil R [0000-0001-7547-4989], Helgason, G Vignir [0000-0003-1616-132X], Huntly, Brian JP [0000-0003-0312-161X], Gallipoli, Paolo [0000-0001-7254-2253], Apollo - University of Cambridge Repository
Rok vydání:	2023
Předmět:	Leukemia Myeloid Acute Multidisciplinary Cell Death fms-Like Tyrosine Kinase 3 Cell Line Tumor Cytarabine General Physics and Astronomy Humans Apoptosis General Chemistry Mannose General Biochemistry Genetics and Molecular Biology
Popis:	Funder: American Society of Hematology (ASH); doi: https://doi.org/10.13039/100001422 Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::759490005d7fd4928880f19e42b86468 https://www.repository.cam.ac.uk/handle/1810/348664 Zobrazit plný text záznamu