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Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment depends on stearoyl-CoA desaturase

Abstract

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty acid synthesis in CNS leukemia, highlighting stearoyl-CoA desaturase (SCD) as a key player. In vivo SCD overexpression increases CNS disease, whereas genetic or pharmacological inhibition of SCD decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.

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Fig. 1: Fatty acid synthesis-related genes are upregulated in CNS-derived ALL cells in xenograft models.
Fig. 2: SCD is upregulated in primary patient samples in the CNS.
Fig. 3: SCD overexpression confirms a competitive advantage for SCD-high cells in the CNS microenvironment.
Fig. 4: SCD ablation decreases 018z cells engraftment in the CNS.
Fig. 5: SCD pharmacological inhibition decreases 018z cells engraftment in the CNS.
Fig. 6: SCD pharmacological inhibition decreases patient-derived xenograft engraftment in the CNS.

Data availability

RNA-seq data supporting this study’s findings have been deposited in GEO (accession number: GSE135115). The GSE135115 SuperSeries is entitled “Gene expression profiles of MLL-AF4 and TEL-AML1 acute lymphoblastic leukemia blasts retrieved from central nervous system and spleen”. This SuperSeries contains two series related to SEM and REH experiments as follows: GSE135113 “Gene expression profiles of MLL-AF4 acute lymphoblastic leukemia blasts retrieved from central nervous system and spleen” and GSE135114 “Gene expression profiles of TEL-AML1 acute lymphoblastic leukemia blasts retrieved from central nervous system and spleen”. Previously published human and primograft data re-analyzed here are available under accession codes GSE60926 and GSE89710. The source data associated with each figure are provided with the manuscript. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank the patients and their families who generously donated the samples used in this study to the NHS Greater Glasgow and Clyde Biorepository, Laboratory Medicine Building, Queen Elizabeth University Hospital, the Bloodwise Childhood Leukemia Cell Bank, the Glasgow Neuroimmunology Biobank and the West of Scotland CSF Biobank. In addition, we thank J. Goodfellow, H. Willison, S. Bhatti and Y. Yousafzai for assistance with obtaining primary samples and C. Orange and L. Stevenson for help with histology. Histology slides were scanned by the University of Glasgow slide scanning and image analysis service at the Queen Elizabeth University Hospital. RNA-seq was performed by the Glasgow Polyomics research facility at the University of Glasgow. We also thank K. Keeshan and the Biological Services Unit, Cancer Research UK Beatson Institute for animal assistance. We thank G. Cazzaniga for supplying PDXs, V. Saha for providing reporter plasmids and L. Akimov, I. Muler, H. Fishman, A. Rein and E. Vax for technical assistance. This work was supported by the Chief Scientist Office (O.O. and C.H., grant ETM/374), Fondazione Italiana per la Ricerca sul Cancro *FIRC (A.M.S.), the William and Elizabeth Davies Foundation (A.C., Clinical Research Fellowship), the Laura and Ike Perlmutter Fund (E.G. and I.A.), the German Israel Foundation (S.I. and C.E.), the Norman and Sadie Lee Foundation (S.I.), the Israel Science Foundation 1775/12 (E.G. and I.M.), European Union ERA NET TRASCALL program (S.I.), Israel Cancer Research Foundation City of Hope collaborative program (S.I.) and Cancer Research UK (J.J.K. and G.M.). This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement META-CAN No 766214 (S.I.F., J.F-G., I.M. and E.G.).

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Authors

Contributions

A.M.S., S.I.F., O.O., E.G., C.H., P.H. and S.I. designed the study. A.M.S., S.I.F., O.O., A.C., A.Z., S.B., I.G., L.F., Y.B., C.E., M.B., E.B. and S.J.R. provided the samples and performed most of the experiments. A.M.S., S.I.F., O.O., A.C., P.H., E.K.M., J.G.-F., C.H., I.M., J.R.C., M.G.K. and E.G. analyzed and interpreted the data. S.T., I.A., J.J.K. and G.M. performed and analyzed the MS experiments. A.M.S., S.I.F., O.O., C.H., E.G., I.M. and S.I. wrote the manuscript.

Corresponding authors

Correspondence to Eyal Gottlieb or Shai Izraeli or Christina Halsey.

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Competing interests

E.G. is a board member and a shareholder of Metabomed Ltd., Israel, J.J.K. is an employee and shareholder of Rheos Medicines Inc. M.G.K. is a consultant for Accent Therapeutics and M.G.K.’s laboratory receives some financial support from 28-7. These disclosures are not directly related to these studies. All other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Leukemic infiltrates in murine CNS and bone marrow.

a, H&E staining of paraffin-embedded leukemic (ALL) murine skull and brain. ** indicates leukemic infiltrate in calvarial bone marrow, dashed line indicates leptomeningeal space filled with leukemic infiltrate b, H&E staining of paraffin embedded murine femur confirming widespread dense leukemic infiltrate throughout the marrow cavity. Images are representative of 8 mice.

Extended Data Fig. 2 Fatty acid synthesis-related genes are upregulated in ALL cells derived from the CNS of xenograft models.

a, Schematic of the RNA Sequencing workflow. Two batches of five NSG mice were xenografted with human ALL cell lines SEM [t(4;11) MLL-AFF1 (MLL-AF4)]. Post engraftment, cells were collected from central nervous system (CNS) and spleens. Before RNA extraction, CNS or spleen ALL cells from each batch were pooled to reach the quantities required for polyA-tailed RNA sequencing. After extraction, RNA was sequenced and analyzed as described in material and methods. b, Top 20 differentially expressed coding genes in CNS compared to spleen from RNA sequencing, excluding genes with a base mean <10, ranked according to their adjusted p-value in SEM (I) and REH (II) cells. Gene function was assigned using NCBI Gene and linked resources. The reported p-value(s) result from a two-sided DESeq2’s Wald test and were FDR-adjusted by the Benjamini-Hochberg procedure. c, I-II Enrichment plots of metabolism of lipids and lipoproteins (REACTOME) and oxidative phosphorylation (KEGG) for REH cell line extracted from the CNS and spleen of engrafted mice (n=2 groups of 5 mice each). Profile of the running ES score & Positions of the Gene Set Members on the Rank Ordered List. III Statistically significant biological functions in REH cells isolated from CNS and spleen of xenografted mice. p-values for positive association with a signature (enrichment) were calculated by permutation test. Plotted are signatures with significant fold-changes in enrichment between the CNS versus spleen groups (log2 scale). Red bars indicate signatures with positive log fold-change (gain) in CNS versus spleen, blue bars indicate negative log fold-change (loss) in CNS versus spleen samples.

Source data

Extended Data Fig. 3 Schematic of the fatty acid metabolism.

Glucose or glutamine-derived citrate or free Acetyl-CoA serve as precursor for saturated fatty acid, further un-saturated to provide either triglycerides or phospholipids. Saturated fatty acids can also enter cycle of degradation within the mitochondrion through beta-oxidation. ACLY: ATP- Citrate Lyase; FASN: Fatty Acid Synthase; SCD: Stearoyl-CoA Desaturase; ACC: Acetyl CoA Carboxylase; CPT: Carnitine Palmitoyltransferase; HMGCR: 3-Hydroxy-3-Methylglutaryl-CoA Reductase; SQLE: Squalene epoxidase; TCA: Tricarboxylic acid cycle; FA: Fatty acid; FAO: Fatty acid oxidation.

Extended Data Fig. 4 Quantitative PCR validation of top ranked genes differentially expressed in CNS blasts compared to spleen in SEM and REH cells.

a, and 018z cells (b) p (two tailed) = one sample T and Wilcoxon test. Results are normalized to 36B4 human housekeeping genes and presented as LogFold2 change enrichment of comparing CNS to spleen for the SEM-REH samples; human HPRT was used as housekeeping gene and enrichment of comparing CNS to BM was calculated for 018z. n=7 for SCD, FASN, ACLY, CPT1a; n=6 for CPT1b; n=5 for CPT2 in (a). n=12 for LDLR, HMGCR, FASN, ACLY, CPT1a, CPT1b; n=11 for SQLE; n=7 for SCD, ABCA1 in b, For box-and-whisker plots, boxes represent 25th and 75th percentiles, center lines indicate median values and whiskers represent minimum and maximum values. c, Western blot of SCD and FASN proteins in SEM cells retrieved from the CNS and spleen of mice (n=4 mice).

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Extended Data Fig. 5 Analysis of available public human databases.

Left side of each panel: Boxplots showing single genes differentially regulated in samples of BM from patients at diagnosis (n=22) and relapse (n=20) and CNS samples at relapse (n=8) from public database GSE60926, unpaired analysis. Right side of each panel: Patient-derived xenograft samples established by transplantation of patient ALL cells onto NSG mice, single dots indicate paired bone marrow and CNS. Public database GSE89710. a, ABCA1: ATP-binding cassette transporter subfamily A member 1; b, ACC: Acetyl-CoA carboxylase; c, ACLY: ATP Citrate Lyase; d, CPT1A: Carnitine Palmitoyltransferase 1A; e, CPT1B: Carnitine Palmitoyltransferase 1B; f, CPT2: Carnitine Palmitoyltransferase 2; g, FASN: Fatty acid synthase; h, HMGCR: 3-Hydroxy-3-Methylglutaryl-CoA Reductase; i, LDLR: Low density lipoprotein receptor; j, SQLE: Squalene. FDR – false discovery rate. For box-and-whisker plots, boxes represent 25th and 75th percentiles, center lines indicate median values and whiskers represent minimum and maximum values.

Source data

Extended Data Fig. 6 Ratios of monounsaturated fatty acids to their saturated precursors.

Ratios of total levels of oleic/stearic acids in total fatty acids extracts in (a) SCD-high and (c) SCD-low 018z cells, in comparison to respective controls (CTL) (n=4 independent experiments for each condition). Ratios of relative levels of oleic/stearic acids in free fatty acids extracts in (b) 018z overexpressing or (d) downregulating SCD, comparatively to corresponding controls (CTL). n=5 independent experiments for each condition, p(two-tailed)=unpaired parametric Student’s t-test. Error bars represent mean ± s.d.

Source data

Extended Data Fig. 7 Increased SCD activity and expression upon genetic modification.

a, Ratio of relative level of oleic/stearic acids in free fatty acids extracts from cells isolated from CNS of mice engrafted with SCD overexpressing (SCD-high, n=3 mice) and control (CTL, n=4 mice) 018z cells. p(two-tailed)=unpaired parametric Student’s t-test. b, Gene expression level of SCD after overexpression in REH cells (n=2 independent experiments). Error bars represent mean ± s.d.

Source data

Extended Data Fig. 8 Effect of FBS delipidation on relative concentrations of metabolites, using fumed silica.

Relative levels of listed metabolites in lipidated (Lip) or delipidated (Delip) FBS – (a) stearic, (b) oleic, (c) palmitic, (d) palmitoleic, (e) arachidonic and (f) linoleic acids, (g) glucose, (h) lactate, (i) glutamine and (j) glutamate. Total fatty acids were extracted by saponification and the polar metabolites were extracted in 50% methanol, 30% acetonitrile, 20% water (“Reg extraction”).

Source data

Extended Data Fig. 9 Body weight of mice treated with SCD1 inhibitor.

Body weight variation of NSG mice transplanted with PDX (a) 1, (b) 2, (c) 3, or (d) 4, treated with SW203668 (Treated, n=5 mice) or vehicle (Control, n=5 mice). Error bars represent mean ± s.d.

Source data

Extended Data Fig. 10 Example of the gating strategy used for flow cytometry analysis.

(a) Gating for live cells. (b) Gating to exclude doublets and cell aggregates. (c) Identification of human and mouse CD45+ specific populations.

Supplementary information

Supplementary Tables 1–5

Reporting Summary

Supplementary Video

Phenotypic representation of SCD overexpression in ALL cells.

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Savino, A.M., Fernandes, S.I., Olivares, O. et al. Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment depends on stearoyl-CoA desaturase. Nat Cancer 1, 998–1009 (2020). https://doi.org/10.1038/s43018-020-00115-2

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