Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells

• Published in: Leukemia 2017-06, Vol.31 (6), p.1434-1442
• Main Authors: Yan, F, Shen, N, Pang, J X, Zhang, Y W, Rao, E Y, Bode, A M, Al-Kali, A, Zhang, D E, Litzow, M R, Li, B, Liu, S J
• Format: Article
• Language: English
• Subjects: 38; 38/109; 631/67/1990/283/1897; 631/67/395; 64/110; 64/60; 82/1; 96/106; Ablation; Acute myelocytic leukemia; Acute myeloid leukemia; Animals; Apoptosis; Binding proteins; Cancer; Cancer Research; Cell fate; Cell growth; Cell Proliferation; Critical Care Medicine; Cytokines; Deoxyribonucleic acid; Development and progression; Diet; Diet, High-Fat - adverse effects; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA methyltransferase; DNMT1 protein; Epigenetics; Fatty acid-binding protein; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Health risks; Hematology; High fat diet; Humans; In vivo methods and tests; Intensive; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Internal Medicine; Laboratory animals; Leukemia; Leukemia, Myeloid, Acute - etiology; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Metabolism; Methylation; Mice; Mice, Inbred C57BL; Molecular modelling; Obesity; Obesity - chemically induced; Obesity - complications; Oncology; original-article; Phosphorylation; Proteins; Risk analysis; Risk factors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transcription factors; Tumor Cells, Cultured; Tumors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.349

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 p15 INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15 INK4B 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.