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

F. Yan, N. Shen, J. X. Pang, Y. W. Zhang, E. Y. Rao, A. M. Bode, A. Al-Kali, D. E. Zhang, Mark R Litzow, B. Li, S. J. Liu

Research output: Contribution to journalArticle

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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.Leukemia advance online publication, 2 December 2016; doi:10.1038/leu.2016.349.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Dec 2 2016

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Fatty Acid-Binding Proteins
Myeloid Cells
DNA Methylation
Acute Myeloid Leukemia
Obesity
Methyltransferases
Leukemia
DNA
Interleukin-6
Up-Regulation
Growth
Transcription Factor 3
STAT3 Transcription Factor
Obese Mice
High Fat Diet
Tumor Suppressor Genes
Publications
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. / Yan, F.; Shen, N.; Pang, J. X.; Zhang, Y. W.; Rao, E. Y.; Bode, A. M.; Al-Kali, A.; Zhang, D. E.; Litzow, Mark R; Li, B.; Liu, S. J.

In: Leukemia, 02.12.2016.

Research output: Contribution to journalArticle

Yan, F. ; Shen, N. ; Pang, J. X. ; Zhang, Y. W. ; Rao, E. Y. ; Bode, A. M. ; Al-Kali, A. ; Zhang, D. E. ; Litzow, Mark R ; Li, B. ; Liu, S. J. / Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. In: Leukemia. 2016.
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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.Leukemia advance online publication, 2 December 2016; doi:10.1038/leu.2016.349.",
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