RT Journal Article
SR Electronic
T1 Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.16.492042
DO 10.1101/2022.05.16.492042
A1 Keith Woodley
A1 Laura S Dillingh
A1 George Giotopoulos
A1 Pedro Madrigal
A1 Kevin M. Rattigan
A1 Celine Philippe
A1 Ryan Asby
A1 Vilma Dembitz
A1 Aoife S.M. Magee
A1 Louie N van de Lagemaat
A1 Christopher Mapperley
A1 Sophie C James
A1 Konstantinos Tzelepis
A1 Kevin Rouault-Pierre
A1 George S. Vassiliou
A1 Kamil R Kranc
A1 Gudmundur Helgason
A1 Brian J.P Huntly
A1 Paolo Gallipoli
YR 2022
UL http://biorxiv.org/content/early/2022/05/16/2022.05.16.492042.abstract
AB Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (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 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 novel 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.Competing Interest StatementThe authors have declared no competing interest.