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

Yan, Fei; Shen, Na; Pang, Jiuxia; Zhang, Y. W.; Rao, Enyu; Bode, Ann M.; Al‐Kali, Aref; Zhang, D. E.; Litzow, Mark R.; Li, B.; Liu, Shujun

doi:10.1038/leu.2016.349

Cited by 79 publications

(122 citation statements)

References 52 publications

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“…Although all three DNMT isoforms are targeted by nilotinib in our cell models, we mainly focused on DNMT1 to delineate the underlying mechanisms because DNMT1 is the most abundant DNMT with both de novo and maintenance DNA methylation activities (22,31). Importantly, although the changes of DNMT3a and DNMT3b displayed variations (not shown), analysis of GEO datasets (i.e., GSE51083, GDS3518, GDS838, GSE19567, GDS4177, GDS4175, GDS2706) supported the idea that DNMT1 downregulation represents one common mechanism behind the anti-leukemia activities of RTK inhibitors (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic DNA was extracted using the DNA Blood/Tissue Kit (QIAGEN) and dotblotting for the quantification of DNA methylation was performed as previously described (22,29,31). Briefly, 2 μg DNA was denatured at 100°C and loaded onto a pre-wet nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

“…The bisulfite sequencing for promoter DNA methylation was performed as previously described (22,29,31). Briefly, the genomic DNA was bisulfite-conversed using the EpiTect Bisulfite Kit (QIAGEN), amplified by PCR and subcloned using the TA cloning Kit (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Shen

Yan

Pang

et al. 2017

Clinical Cancer Research

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Purpose Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors. Experimental Design Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice and in nilotinib-treated leukemia patients were determined. Results Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased, DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression. Conclusions Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Shen

Yan

Pang

et al. 2017

Clinical Cancer Research

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“…However, how TQ manifests these activities is not fully understood, although it has been shown to downregulate the expression of Bcl-xL [18], COX-2 [19], iNOS [20], 5-LOX [21], TNF [22] and cyclin D1 [16], all known to be regulated by NFkB activity that can be blocked by TQ [23]. Given the regulatory role of NFkB in DNMT1 expression [1, 2, 24], these investigations support the notion that TQ may influence epigenetic events in cancer cells, which has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells

et al. 2017

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Thymoquinone (TQ), a bioactive constituent of the volatile oil of Monarda fistulosa and Nigella sativa, possesses cancer-specific growth inhibitory effects, but the underlying molecular mechanisms remain largely elusive. We propose that TQ curbs cancer cell growth through dysfunction of DNA methyltransferase 1 (DNMT1). Molecular docking analysis revealed that TQ might interact with the catalytic pocket of DNMT1 and compete with co-factor SAM/SAH for DNMT1 inhibition. In vitro inhibitory assays showed that TQ decreases DNMT1 methylation activity in a dose-dependent manner with an apparent IC50 of 30 nM. Further, exposure of leukemia cell lines and patient primary cells to TQ resulted in DNMT1 downregulation, mechanistically, through dissociation of Sp1/NFkB complex from DNMT1 promoter. This led to a reduction of DNA methylation, a decrease of colony formation and an increase of cell apoptosis via the activation of caspases. In addition, we developed and validated a sensitive and specific LC-MS/MS method and successfully detected a dynamic change of TQ in mouse plasma after administration of TQ through the tail vein, and determined a tolerable dose of TQ to be 15 mg/kg in mouse. TQ administration into leukemia-bearing mice induced leukemia regression, as indicated by the reversed splenomegaly and the inhibited leukemia cell growth in lungs and livers. Our study for the first time demonstrates that DNMT1-dependent DNA methylation mediates the anticancer actions of TQ, opening a window to develop TQ as a novel DNA hypomethylating agent for leukemia therapy.

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“…Due to the known relationship between obesity and outcome in pediatric AML and recent evidence suggesting that IL-6 may have a role in fatty acid metabolism and obesity, 27 we further interrogated our data for correlations between clinical characteristics and IL-6 levels. Body mass index did not correlate with IL-6 levels (supplemental Figure 4A; Spearman R 5 0.1244, P 5 .2562, n 5 30).…”

Section: Il-6 Levels and Clinical Characteristics Including Body Massmentioning

confidence: 99%

Interleukin-6 levels predict event-free survival in pediatric AML and suggest a mechanism of chemotherapy resistance

Stevens¹,

Miller

Munoz³

et al. 2017

Blood Advances

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Key Points• IL-6 levels in bone marrow predict event-free survival in pediatric AML.• Exogenous IL-6 protects AML blasts from chemotherapy-induced apoptosis.The tumor microenvironment can protect cancer cells from conventional anticancer therapies. Thus, targeting these protective mechanisms could eradicate therapy-resistant cancer cells and improve outcomes. Interleukin-6 (IL-6) provides extrinsic protection for several solid tumors and multiple myeloma. In pediatric acute myeloid leukemia (AML), IL-6-induced STAT3 signaling frequently becomes stronger at relapse, and increases in IL-6-induced STAT3 activity are associated with inferior survival after relapse. These findings suggested that the IL-6-induced STAT3 pathway may promote chemotherapy resistance and disease progression. Thus, we investigated the dysregulation of IL-6 levels in the bone marrow niche in pediatric patients with AML and the association between IL-6 levels and outcome. We measured levels of over 40 cytokines and growth factors in plasma from diagnostic bone marrow aspirates of 45 pediatric AML patients and 7 healthy sibling controls. Of the measured cytokines, only IL-6 levels were associated with event-free survival. Importantly, the effect of elevated IL-6 was most striking among children classified as having a low risk of relapse. In these patients, 5-year event-free survival was 82.5% 6 11% for patients with low IL-6 levels at diagnosis (n 5 14) compared with 17.3% 6 11% for patients with elevated IL-6 (n 5 13, log-rank P 5 .0003). In vitro, exogenous IL-6 reduced mitoxantrone-induced apoptosis in cell lines and primary pediatric AML samples. These results suggest that IL-6 levels at diagnosis could be used to help identify children at high risk of relapse, particularly those who are otherwise classified as low risk by current algorithms.Moreover, the IL-6 pathway could represent a target for overcoming environment-mediated chemotherapy resistance.

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

Cited by 79 publications

References 52 publications

Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells

Interleukin-6 levels predict event-free survival in pediatric AML and suggest a mechanism of chemotherapy resistance

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