Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells
Balasundaram, N.; Erdem, A.; Sharda, A.; Daniëls, V. W.; Chea, P. L.; Leguay, F.; Liu, Y.; Keibler, M. A.; Vidoudez, C.; Lane, A. A.; Vertommen, D.; Casteur, H.; Laurent, M.; Trauger, S. A.; Stephanopoulos, G.; Scadden, D. T.; van Gastel, N.
Show abstract
Though cancer cells altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth 96%
- Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells 95%
- Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death. 95%
Similar papers in this journal
- Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma 96%
- Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth 95%
- Defective ribosome assembly impairs leukemia stem cell function in a murine model of acute myeloid leukemia 95%
Similar papers in this journal
- SCD inhibition eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy 96%
- AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML 96%
- Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network 96%
Similar papers in this journal
- Reprogramming of serine metabolism is an actionable vulnerability in FLT3-ITD driven acute myeloid leukaemia 96%
- Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia 96%
- Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.