Abstract
Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.
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References
Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D et al. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 2002; 22: 2124–2135.
Shen N, Yan F, Pang J, Wu LC, Al-Kali A, Litzow MR et al. A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. Oncotarget 2014; 5: 5494–5509.
Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 2009; 113: 6411–6418.
Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E et al. Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood 2008; 111: 2364–2373.
Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell 2012; 22: 645–655.
Gao XN, Yan F, Lin J, Gao L, Lu XL, Wei SC et al. AML1/ETO cooperates with HIF1alpha to promote leukemogenesis through DNMT3a transactivation. Leukemia 2015; 29: 1730–1740.
Liu S . Epigenetics advancing personalized nanomedicine in cancer therapy. Adv Drug Deliv Rev 2012; 64: 1532–1543.
Aguilera O, Fernandez AF, Munoz A, Fraga MF . Epigenetics and environment: a complex relationship. J Appl Physiol 2010; 109: 243–251.
Balkwill F, Charles KA, Mantovani A . Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005; 7: 211–217.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–1808.
Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.
Lu H, Ouyang W, Huang C . Inflammation, a key event in cancer development. Mol Cancer Res 2006; 4: 221–233.
Castillo JJ, Reagan JL, Ingham RR, Furman M, Dalia S, Merhi B et al. Obesity but not overweight increases the incidence and mortality of leukemia in adults: a meta-analysis of prospective cohort studies. Leuk Res 2012; 36: 868–875.
Lichtman MA . Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist 2010; 15: 1083–1101.
Poynter JN, Richardson M, Blair CK, Roesler MA, Hirsch BA, Nguyen P et al. Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes. Cancer Epidemiol 2016; 40: 134–140.
Furuhashi M, Hotamisligil GS . Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008; 7: 489–503.
Storch J, Corsico B . The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr 2008; 28: 73–95.
Terra X, Quintero Y, Auguet T, Porras JA, Hernandez M, Sabench F et al. FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. Eur J Endocrinol 2011; 164: 539–547.
Furuhashi M, Fucho R, Gorgun CZ, Tuncman G, Cao H, Hotamisligil GS . Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest 2008; 118: 2640–2650.
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17: 1498–1503.
Lee D, Wada K, Taniguchi Y, Al-Shareef H, Masuda T, Usami Y et al. Expression of fatty acid binding protein 4 is involved in the cell growth of oral squamous cell carcinoma. Oncol Rep 2014; 31: 1116–1120.
Hancke K, Grubeck D, Hauser N, Kreienberg R, Weiss JM . Adipocyte fatty acid-binding protein as a novel prognostic factor in obese breast cancer patients. Breast Cancer Res Treat 2010; 119: 367–367.
Wu LE, Samocha-Bonet D, Whitworth PT, Fazakerley DJ, Turner N, Biden TJ et al. Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity. Mol Metab 2014; 3: 465–473.
Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 2013; 17: 768–778.
Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006; 52: 405–413.
Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 2006; 12: 945–949.
Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland MC et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood 2008; 112: 4193–4201.
Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 2010; 16: 903–908.
Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y et al. Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 2001; 97: 1172–1179.
Tholouli E, MacDermott S, Hoyland J, Yin JL, Byers R . Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia. Biochem Biophys Res Commun 2012; 425: 333–339.
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G . Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280: E745–E751.
Jhun JY, Yoon BY, Park MK, Oh HJ, Byun JK, Lee SY et al. Obesity aggravates the joint inflammation in a collagen-induced arthritis model through deviation to Th17 differentiation. Exp Mol Med 2012; 44: 424–431.
Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A et al. Raised interleukin-6 levels in obese patients. Obes Res 2000; 8: 673–675.
Makowski L, Brittingham KC, Reynolds JM, Suttles J, Hotamisligil GS . The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J Biol Chem 2005; 280: 12888–12895.
Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Banas H et al. Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine 2013; 61: 885–891.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009; 15: 103–113.
Robertson KD . DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20: 3139–3155.
Larsson SC, Wolk A . Overweight and obesity and incidence of leukemia: a meta-analysis of cohort studies. Int J Cancer 2008; 122: 1418–1421.
Wenzell CM, Gallagher EM, Earl M, Yeh JY, Kusick KN, Advani AS et al. Outcomes in obese and overweight acute myeloid leukemia patients receiving chemotherapy dosed according to actual body weight. Am J Hematol 2013; 88: 906–909.
Medeiros BC, Othus M, Estey EH, Fang M, Appelbaum FR . Impact of body-mass index on the outcome of adult patients with acute myeloid leukemia. Haematologica 2012; 97: 1401–1404.
Lee HJ, Licht AS, Hyland AJ, Ford LA, Sait SN, Block AW et al. Is obesity a prognostic factor for acute myeloid leukemia outcome? Ann Hematol 2012; 91: 359–365.
Rosner GL, Hargis JB, Hollis DR, Budman DR, Weiss RB, Henderson IC et al. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J Clin Oncol 1996; 14: 3000–3008.
Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97–101.
Vucenik I, Stains JP . Obesity and cancer risk: evidence, mechanisms, and recommendations. Ann NY Acad Sci 2012; 1271: 37–43.
Hertzel AV, Smith LA, Berg AH, Cline GW, Shulman GI, Scherer PE et al. Lipid metabolism and adipokine levels in fatty acid-binding protein null and transgenic mice. Am J Physiol Endocrinol Metab 2006; 290: E814–E823.
Sonnet M, Claus R, Becker N, Zucknick M, Petersen J, Lipka DB et al. Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia. Genome Med 2014; 6: 34.
Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y . Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466: 1129–1133.
Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468: 839–843.
Fritz EL, Papavasiliou FN . Cytidine deaminases: AIDing DNA demethylation? Genes Dev 2010; 24: 2107–2114.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.
Acknowledgements
This work was supported partially by The Hormel Foundation, National Cancer Institute (Bethesda, MD, USA) grants R01CA149623, R01CA177679, R01CA180986, R01CA104509, R21CA155915 and R03CA186176-01A1, Career Transition Fellowship (NMSS TA3047-A-1) and the Predolin Foundation. We thank Dr Jill Suttles for providing Fabp4-deficient mice, Dr Clara Nervi for providing the SKNO-1 cell line and Dr Margot P. Cleary at The Hormel Institute University of Minnesota for assistance in proofreading.
Author contributions
BL and SJL conceived ideas and designed the experiments; FY, NS, JXP, YWZ, SCW and EYR performed experiments; AA and MRL provided the leukemia patient samples; DEZ provided the AML1/ETO9a mouse model and critically reviewed the paper; FY, AMB, AA-K, MRL, BL and SJL analyzed data and wrote the paper; FY carried out the biostatistical analysis; and SJL oversaw the entire research project.
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Yan, F., Shen, N., Pang, J. et al. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia 31, 1434–1442 (2017). https://doi.org/10.1038/leu.2016.349
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DOI: https://doi.org/10.1038/leu.2016.349
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