title: 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 p15INK4Btumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4Bexpression, 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.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yan
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: J X
authors.initials: JX
authors.lastname: Pang
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Y W
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Rao
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Hematology Division, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Al-Kali
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.|Division of Biological Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Zhang
authors.affiliation: Hematology Division, Mayo Clinic, Rochester, MN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D059305:Diet, High-Fat / Q000009:adverse effects; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced / Q000150:complications*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases