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Transcriptional control and signal transduction, cell cycle

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

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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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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Correspondence to S J Liu.

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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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