Recent advances in lipid metabolism of acute leukemia_West China Medical Journal

Authors：

DONG Shaojuan ¹ , CUI Mengying ¹ , HE Li ¹ , BAO Ying ¹ , ZHU Danxia ² , WU Jun ² ,  CHEN Ye ¹

1. Department of Hematology, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, P. R. China;
2. Department of Oncology, the Third Affiliated Hospital of Soochow University / Changzhou First People’s Hospital, Changzhou, Jiangsu 213003, P. R. China;

Corresponding author：

CHEN Ye, Email: 949399787@qq.com

Keywords：

Acute leukemia; lipid metabolism reprogramming; targeted metabolism; targeted therapy; chemotherapy resistance

DOI：

10.7507/1002-0179.202402114

Video：

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The poor treatment effect and short survival period of patients with acute leukemia are mainly due to the lack of effective early diagnosis and treatment targets. Lipid metabolism reprogramming meets the material and energy requirements for rapid proliferation and division of tumor cells, and is associated with the invasiveness, recurrence, and chemotherapy resistance of acute leukemia. This article reviews the carcinogenic and chemotherapy resistance mechanisms of lipid metabolism reprogramming in leukemia cells, and summarizes the latest findings on targeted fatty acid metabolism pathways, aiming to provide a new perspective on the role of intracellular fatty acid metabolism in the occurrence and development of acute leukemia. It is expected to provide a theoretical basis for the elucidation of its resistance mechanism and the development of corresponding targeted therapies.

Citation： DONG Shaojuan, CUI Mengying, HE Li, BAO Ying, ZHU Danxia, WU Jun, CHEN Ye. Recent advances in lipid metabolism of acute leukemia. West China Medical Journal, 2024, 39(7): 1162-1167. doi: 10.7507/1002-0179.202402114 Copy

1.	Mohamed Jiffry MZ, Kloss R, Ahmed-Khan M, et al. A review of treatment options employed in relapsed/refractory AML. Hematology, 2023, 28(1): 2196482.
2.	Bewersdorf JP, Abdel-Wahab O. Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic. Genes Dev, 2022, 36(5/6): 259-277.
3.	Wang J, Li Y. CD36 tango in cancer: signaling pathways and functions. Theranostics, 2019, 9(17): 4893-4908.
4.	Farge T, Nakhle J, Lagarde D, et al. CD36 drives metastasis and relapse in acute myeloid leukemia. Cancer Res, 2023, 83(17): 2824-2838.
5.	Zhang Y, Guo H, Zhang Z, et al. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia. Exp Cell Res, 2022, 415(1): 113112.
6.	Newton JG, Horan JT, Newman S, et al. CD36-positive B-lymphoblasts predict poor outcome in children with B-lymphoblastic leukemia. Pediatr Dev Pathol, 2017, 20(3): 224-231.
7.	Feng X, Zhang L, Xu S, et al. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog Lipid Res, 2020, 77: 101006.
8.	Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res, 2009, 50: S138-S143.
9.	da Silva-Diz V, Singh A, Lancho O, et al. Therapeutic targeting of ACLY in T-ALL in vivo. bioRxiv, 2023: 534395.
10.	Anderson R, Pladna KM, Schramm NJ, et al. Pyruvate dehydrogenase inhibition leads to decreased glycolysis, increased reliance on gluconeogenesis and alternative sources of acetyl-CoA in acute myeloid leukemia. Cancers (Basel), 2023, 15(2): 484.
11.	Wang J, Ye W, Yan X, et al. Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia. J Transl Med, 2019, 17(1): 149.
12.	Wang Y, Yu W, Li S, et al. Acetyl-CoA carboxylases and diseases. Front Oncol, 2022, 12: 836058.
13.	Ito H, Nakamae I, Kato JY, et al. Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development. J Clin Invest, 2021, 131(12): e141529.
14.	Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab, 2020, 31(1): 62-76.
15.	Southam AD, Khanim FL, Hayden RE, et al. Drug redeployment to kill leukemia and lymphoma cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids. Cancer Res, 2015, 75(12): 2530-2540.
16.	Samudio I, Harmancey R, Fiegl M, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest, 2010, 120(1): 142-156.
17.	Subedi A, Liu Q, Ayyathan DM, et al. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell, 2021, 28(10): 1851-1867. e8.
18.	Cioccoloni G, Aquino A, Notarnicola M, et al. Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line. J Chemother, 2020, 32(1): 30-40.
19.	Ventura R, Mordec K, Waszczuk J, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine, 2015, 2(8): 808-824.
20.	Martin MW, Lancia DR Jr, Li H, et al. Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN). Bioorg Med Chem Lett, 2019, 29(8): 1001-1006.
21.	Karakitsou E, Foguet C, Contreras Mostazo MG, et al. Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy. Comput Struct Biotechnol J, 2021, 19: 4059-4066.
22.	Nazih H, Bard JM. Cholesterol, oxysterols and LXRs in breast cancer pathophysiology. Int J Mol Sci, 2020, 21(4): 1356.
23.	Zou H, Yang N, Zhang X, et al. RORγ is a context-specific master regulator of cholesterol biosynthesis and an emerging therapeutic target in cancer and autoimmune diseases. Biochem Pharmacol, 2022, 196: 114725.
24.	Yang HX, Zhang M, Long SY, et al. Cholesterol in LDL receptor recycling and degradation. Clin Chim Acta, 2020, 500: 81-86.
25.	Mouchel PL, Serhan N, Betous R, et al. Dendrogenin A enhances anti-leukemic effect of anthracycline in acute myeloid leukemia. Cancers (Basel), 2020, 12(10): 2933.
26.	Pandyra A, Mullen PJ, Kalkat M, et al. Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Res, 2014, 74(17): 4772-4782.
27.	Zhou C, Li J, Du J, et al. HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis. Biomed Pharmacother, 2021, 137: 111378.
28.	Hong CS, Jeong E, Boyiadzis M, et al. Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia. J Extracell Vesicles, 2020, 9(1): 1800979.
29.	Wang Z, Wang Y, Li Z, et al. Lipid metabolism as a target for cancer drug resistance: progress and prospects. Front Pharmacol, 2023, 14: 1274335.
30.	Zhang H, Wang Y, Guan L, et al. Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence. J Pharm Anal, 2021, 11(3): 340-350.
31.	Salunkhe S, Mishra SV, Ghorai A, et al. Metabolic rewiring in drug resistant cells exhibit higher OXPHOS and fatty acids as preferred major source to cellular energetics. Biochim Biophys Acta Bioenerg, 2020, 1861(12): 148300.
32.	Grønningsæter IS, Reikvam H, Aasebø E, et al. Targeting cellular metabolism in acute myeloid leukemia and the role of patient heterogeneity. Cells, 2020, 9(5): 1155.
33.	Ricciardi MR, Mirabilii S, Allegretti M, et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood, 2015, 126(16): 1925-1929.
34.	Stäubert C, Bhuiyan H, Lindahl A, et al. Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine. J Biol Chem, 2015, 290(13): 8348-8359.
35.	Lee EA, Angka L, Rota SG, et al. Targeting mitochondria with avocatin b induces selective leukemia cell death. Cancer Res, 2015, 75(12): 2478-2488.
36.	Tcheng M, Roma A, Ahmed N, et al. Very long chain fatty acid metabolism is required in acute myeloid leukemia. Blood, 2021, 137(25): 3518-3532.
37.	Stevens BM, Jones CL, Pollyea DA, et al. Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer, 2020, 1(12): 1176-1187.
38.	贾睿楠. CD34⁺细胞的异质性和骨髓微环境脂肪细胞在急性白血病中的作用及机制研究. 济南: 山东大学, 2022.
39.	陈瑶, 庄海慧, 陆瑜钰, 等. 脂肪酸代谢在急性髓系白血病中的研究进展. 生命的化学, 2022, 42(7): 1365-1372.
40.	刘羿晨, 杜婷婷, 王庆华, 等. 脂质代谢与血液肿瘤. 药学学报, 2021, 56(9): 2456-2463.
41.	Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer, 2021, 21(12): 753-766.
42.	Stuani L, Riols F, Millard P, et al. Stable isotope labeling highlights enhanced fatty acid and lipid metabolism in human acute myeloid leukemia. Int J Mol Sci, 2018, 19(11): 3325.
43.	Tabe Y, Yamamoto S, Saitoh K, et al. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res, 2017, 77(6): 1453-1464.
44.	Matsushita Y, Nakagawa H, Koike K. Lipid metabolism in oncology: why it matters, how to research, and how to treat. Cancers (Basel), 2021, 13(3): 474.
45.	Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab, 2020, 2(2): 132-141.
46.	Sharma P, Borthakur G. Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia. Cancer Drug Resist, 2023, 6(3): 567-589.
47.	Ye H, Adane B, Khan N, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell, 2016, 19(1): 23-37.
48.	Tucci J, Chen T, Margulis K, et al. Adipocytes provide fatty acids to acute lymphoblastic leukemia cells. Front Oncol, 2021, 11: 665763.

1. Mohamed Jiffry MZ, Kloss R, Ahmed-Khan M, et al. A review of treatment options employed in relapsed/refractory AML. Hematology, 2023, 28(1): 2196482.
2. Bewersdorf JP, Abdel-Wahab O. Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic. Genes Dev, 2022, 36(5/6): 259-277.
3. Wang J, Li Y. CD36 tango in cancer: signaling pathways and functions. Theranostics, 2019, 9(17): 4893-4908.
4. Farge T, Nakhle J, Lagarde D, et al. CD36 drives metastasis and relapse in acute myeloid leukemia. Cancer Res, 2023, 83(17): 2824-2838.
5. Zhang Y, Guo H, Zhang Z, et al. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia. Exp Cell Res, 2022, 415(1): 113112.
6. Newton JG, Horan JT, Newman S, et al. CD36-positive B-lymphoblasts predict poor outcome in children with B-lymphoblastic leukemia. Pediatr Dev Pathol, 2017, 20(3): 224-231.
7. Feng X, Zhang L, Xu S, et al. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog Lipid Res, 2020, 77: 101006.
8. Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res, 2009, 50: S138-S143.
9. da Silva-Diz V, Singh A, Lancho O, et al. Therapeutic targeting of ACLY in T-ALL in vivo. bioRxiv, 2023: 534395.
10. Anderson R, Pladna KM, Schramm NJ, et al. Pyruvate dehydrogenase inhibition leads to decreased glycolysis, increased reliance on gluconeogenesis and alternative sources of acetyl-CoA in acute myeloid leukemia. Cancers (Basel), 2023, 15(2): 484.
11. Wang J, Ye W, Yan X, et al. Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia. J Transl Med, 2019, 17(1): 149.
12. Wang Y, Yu W, Li S, et al. Acetyl-CoA carboxylases and diseases. Front Oncol, 2022, 12: 836058.
13. Ito H, Nakamae I, Kato JY, et al. Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development. J Clin Invest, 2021, 131(12): e141529.
14. Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab, 2020, 31(1): 62-76.
15. Southam AD, Khanim FL, Hayden RE, et al. Drug redeployment to kill leukemia and lymphoma cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids. Cancer Res, 2015, 75(12): 2530-2540.
16. Samudio I, Harmancey R, Fiegl M, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest, 2010, 120(1): 142-156.
17. Subedi A, Liu Q, Ayyathan DM, et al. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell, 2021, 28(10): 1851-1867. e8.
18. Cioccoloni G, Aquino A, Notarnicola M, et al. Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line. J Chemother, 2020, 32(1): 30-40.
19. Ventura R, Mordec K, Waszczuk J, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine, 2015, 2(8): 808-824.
20. Martin MW, Lancia DR Jr, Li H, et al. Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN). Bioorg Med Chem Lett, 2019, 29(8): 1001-1006.
21. Karakitsou E, Foguet C, Contreras Mostazo MG, et al. Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy. Comput Struct Biotechnol J, 2021, 19: 4059-4066.
22. Nazih H, Bard JM. Cholesterol, oxysterols and LXRs in breast cancer pathophysiology. Int J Mol Sci, 2020, 21(4): 1356.
23. Zou H, Yang N, Zhang X, et al. RORγ is a context-specific master regulator of cholesterol biosynthesis and an emerging therapeutic target in cancer and autoimmune diseases. Biochem Pharmacol, 2022, 196: 114725.
24. Yang HX, Zhang M, Long SY, et al. Cholesterol in LDL receptor recycling and degradation. Clin Chim Acta, 2020, 500: 81-86.
25. Mouchel PL, Serhan N, Betous R, et al. Dendrogenin A enhances anti-leukemic effect of anthracycline in acute myeloid leukemia. Cancers (Basel), 2020, 12(10): 2933.
26. Pandyra A, Mullen PJ, Kalkat M, et al. Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Res, 2014, 74(17): 4772-4782.
27. Zhou C, Li J, Du J, et al. HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis. Biomed Pharmacother, 2021, 137: 111378.
28. Hong CS, Jeong E, Boyiadzis M, et al. Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia. J Extracell Vesicles, 2020, 9(1): 1800979.
29. Wang Z, Wang Y, Li Z, et al. Lipid metabolism as a target for cancer drug resistance: progress and prospects. Front Pharmacol, 2023, 14: 1274335.
30. Zhang H, Wang Y, Guan L, et al. Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence. J Pharm Anal, 2021, 11(3): 340-350.
31. Salunkhe S, Mishra SV, Ghorai A, et al. Metabolic rewiring in drug resistant cells exhibit higher OXPHOS and fatty acids as preferred major source to cellular energetics. Biochim Biophys Acta Bioenerg, 2020, 1861(12): 148300.
32. Grønningsæter IS, Reikvam H, Aasebø E, et al. Targeting cellular metabolism in acute myeloid leukemia and the role of patient heterogeneity. Cells, 2020, 9(5): 1155.
33. Ricciardi MR, Mirabilii S, Allegretti M, et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood, 2015, 126(16): 1925-1929.
34. Stäubert C, Bhuiyan H, Lindahl A, et al. Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine. J Biol Chem, 2015, 290(13): 8348-8359.
35. Lee EA, Angka L, Rota SG, et al. Targeting mitochondria with avocatin b induces selective leukemia cell death. Cancer Res, 2015, 75(12): 2478-2488.
36. Tcheng M, Roma A, Ahmed N, et al. Very long chain fatty acid metabolism is required in acute myeloid leukemia. Blood, 2021, 137(25): 3518-3532.
37. Stevens BM, Jones CL, Pollyea DA, et al. Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer, 2020, 1(12): 1176-1187.
38. 贾睿楠. CD34⁺细胞的异质性和骨髓微环境脂肪细胞在急性白血病中的作用及机制研究. 济南: 山东大学, 2022.
39. 陈瑶, 庄海慧, 陆瑜钰, 等. 脂肪酸代谢在急性髓系白血病中的研究进展. 生命的化学, 2022, 42(7): 1365-1372.
40. 刘羿晨, 杜婷婷, 王庆华, 等. 脂质代谢与血液肿瘤. 药学学报, 2021, 56(9): 2456-2463.
41. Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer, 2021, 21(12): 753-766.
42. Stuani L, Riols F, Millard P, et al. Stable isotope labeling highlights enhanced fatty acid and lipid metabolism in human acute myeloid leukemia. Int J Mol Sci, 2018, 19(11): 3325.
43. Tabe Y, Yamamoto S, Saitoh K, et al. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res, 2017, 77(6): 1453-1464.
44. Matsushita Y, Nakagawa H, Koike K. Lipid metabolism in oncology: why it matters, how to research, and how to treat. Cancers (Basel), 2021, 13(3): 474.
45. Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab, 2020, 2(2): 132-141.
46. Sharma P, Borthakur G. Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia. Cancer Drug Resist, 2023, 6(3): 567-589.
47. Ye H, Adane B, Khan N, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell, 2016, 19(1): 23-37.
48. Tucci J, Chen T, Margulis K, et al. Adipocytes provide fatty acids to acute lymphoblastic leukemia cells. Front Oncol, 2021, 11: 665763.

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Recent advances in lipid metabolism of acute leukemia

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