AML1–ETO promotes SIRT1 expression to enhance leukemogenesis of t(8;21) acute myeloid leukemia

Zhou, Lei; Wang, Qin; Chen, Xiaosu; Fu, Lin; Zhang, Xiaodong; Wang, Lijun; Deng, Ailing; Li, Dandan; Liu, Jing; Lv, Na; Wang, Lili; Li, Yonghui; Liu, Dai‐Hong; Yu, Li; Dou, Liping

doi:10.1016/j.exphem.2016.09.013

Cited by 12 publications

(9 citation statements)

References 27 publications

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“…As a transcription factor, the A/E fusion protein plays a critical role in the pathogenesis of t(8;21) AML and regulates gene expression through various mechanisms, that is, by direct DNA binding and recruitment of DNMTs, HDACs, P300, and PRMT1; 12 , 18 – 20 by interacting with other transcription factors; 15 , 21 , 22 or by forming stable multiprotein complexes, including CBFβ/HEB/E2A/LYL1/AML1 23 . Our previous studies showed that A/E can bind to the promoters of miR-9-1 and SIRT1 to form a regulatory circuit, resulting in the down-regulation of miR-9 and upregulation of SIRT1 and contributing to leukemogenesis 15 , 17 . In this study, we showed for the first time that hypermethylation of the BASP1 gene promoter leads to specific down-regulation of BASP1 in t(8;21) AML.…”

Section: Discussionmentioning

confidence: 99%

“…Chromatin immunoprecipitation (ChIP) assays were performed as described previously using the EZ-ChIP Assay Kit (Millipore, Billerica, MA, USA) according to the manufacturer’s instructions 15 . Briefly, SKNO-1 and SKNO-1-siA/E cells were seeded at a density of 2 × 10 6 and incubated for 10 min at 37 °C to crosslink the proteins to DNA after treatment with formaldehyde (1% final concentration).…”

Section: Methodsmentioning

confidence: 99%

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Methylation-associated silencing of BASP1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Zhou

et al. 2018

Exp Mol Med

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The AML1-ETO fusion protein (A/E), which results from the t(8;21) translocation, is considered to be a leukemia-initiating event. Identifying the mechanisms underlying the oncogenic activity of A/E remains a major challenge. In this study, we identified a specific down-regulation of brain acid-soluble protein 1 (BASP1) in t(8;21) acute myeloid leukemia (AML). A/E recognized AML1-binding sites and recruited DNA methyltransferase 3a (DNMT3a) to the BASP1 promoter sequence, which triggered DNA methylation-mediated silencing of BASP1. Ectopic expression of BASP1 inhibited proliferation and the colony-forming ability of A/E-positive AML cell lines and led to apoptosis and cell cycle arrest. The DNMT inhibitor decitabine up-regulated the expression of BASP1 in A/E-positive AML cell lines. In conclusion, our data suggest that BASP1 silencing via promoter methylation may be involved in A/E-mediated leukemogenesis and that BASP1 targeting may be an actionable therapeutic strategy in t(8;21) AML.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Methylation-associated silencing of BASP1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Zhou

et al. 2018

Exp Mol Med

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“…Recently, several studies reported that the RUNX1–ETO protein interacts with P300 at the docking site provided by the ETO NHR1 domain, and induces upregulation of target genes (e.g. p21 , Egr1 , and SIRT1 ) . P300 has histone acetyltransferase activity, which leads to the relaxation of the DNA chromatin structure, making chromosomes accessible and causing transcriptional activation of downstream target genes .…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that RUNX1–ETO increases c‐KIT promoter activity through directly binding to the promoter region via the RUNX1 motifs located at +655 and +674 relative to the TSS . However, RUNX1–ETO regulated downstream genes miR‐193a , DNMT3a , and SIRT1 by binding to the promoter region (−280 bp, −1890 to −1821 bp, and −546 bp realtive to the TSS) , and as is well known, promoter sequences are usually the sequence upstream of the TSS and play an important role for transcriptional regulation. Therefore, the RUNX1 binding site (−953 bp relative to the TSS) on the c‐KIT promoter may be another potential therapeutic site.…”

Section: Discussionmentioning

confidence: 99%

The RUNX1–ETO fusion protein trans‐activates c‐KIT expression by recruiting histone acetyltransferase P300 on its promoter

Chen

Liu

et al. 2019

The FEBS Journal

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The oncoprotein RUNX1–ETO is the fusion product of t(8;21)(q22;q22) and constitutes one of the most common genetic alterations in acute myeloid leukemia (AML). Abnormal c‐KIT overexpression is considered an independent negative prognostic factor for relapse and survival in t(8;21) AML patients. However, the molecular mechanism of high c‐KIT expression in t(8;21) AML remains unknown. In this study, we detected RUNX1–ETO and c‐KIT gene expression in AML‐M2 patients and verified the overexpression of c‐KIT in t(8;21) AML patients. We also found that c‐KIT overexpression was a poor prognostic indicator in RUNX1–ETO positive AML patients, but not in RUNX1–ETO negative AML patients. We used the dual‐luciferase and ChIP assays to demonstrate that the RUNX1–ETO protein epigenetically trans‐activates c‐KIT by binding to the c‐KIT promoter and recruiting the histone acetyltransferase P300 to the c‐KIT promoter, elucidating the mechanism of the abnormally increased c‐KIT expression in t(8;21) AML patients. Moreover, pharmacological studies revealed that C646, a P300 inhibitor, could inhibit proliferation, induce apoptosis and arrest the cell cycle more effectively in RUNX1–ETO positive cells than in negative ones. The levels of c‐KIT and RUNX1–ETO proteins were also decreased with C646 treatment in RUNX1–ETO positive cells. These findings suggested that P300 could be a therapeutic target and that C646 could be used as a potential treatment for RUNX1–ETO positive AML patients. Interestingly, using the dual‐luciferase assay, we also found that the binding capacity of RUNX1–ETO9a, a truncated RUNX1–ETO isoform, to the c‐KIT promoter was stronger than that of RUNX1–ETO, suggesting RUNX1–ETO9a as another valuable therapeutic target in t(8;21) AML.

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“…Furthermore, SIRT1 activation promotes the maintenance and drug resistance of human FLT3-internal tandem duplication in acute myeloid leukemia stem cells (25). Inhibition of SIRT1 induces G1 arrest, apoptosis and inhibits the proliferation of acute myeloid gene 1 and myeloid transforming gene 8)-positive cells (26). Furthermore, targeting SIRT1 induces CML sensitivity to TKI treatment via the activation of p53 (27).…”

Section: Introductionmentioning

confidence: 99%

Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling

Gao

Liu

et al. 2020

Exp Ther Med

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Targeting multiple signaling pathways is a potential novel therapeutic strategy for the treatment of leukemias. Leukemia cells express high levels of sphingosine kinase 1 (Sphk1) and sirtuin 1 (SIRT1). However, to the best of our knowledge, their interaction and potential synergistic inhibitory effects on the growth and survival of leukemia cells have not been investigated. The present study revealed the role of the Sphk1/S1P/SIRT1 axis in K562, KCL22 and TF1 cells and hypothesized that the inhibition of Sphk1 and SIRT1 had synergistic effects on the growth and survival of leukemia cells. Cell viability was tested using a Cell Counting Kit-8 assay and cell colony forming assay. Cell apoptosis was detected using Annexin V-APC/PI staining. The stages of the cell cycle were measured using PI staining. Protein levels were measured by western blotting. Treatment of leukemia cells with S1P resulted in the upregulation of SIRT1 expression, whereas inhibition of Sphk1 induced SIRT1 downregulation in leukemia cells. Both SKI-II and EX527 actively suppressed growth, blocked cell cycle progression and induced apoptosis of leukemia cells. Furthermore, inhibition of Sphk1 and SIRT1 exhibited suppressive effects on the growth and survival of leukemia cells. Notably, the inhibition of Sphk1 and SIRT1 suppressed cell growth and induced apoptosis of T-315I mutation-harboring cells. Additionally, treatment with SKI-II and EX527 suppressed the ERK and STAT5 pathways in leukemia cells. These data indicated that targeting the Sphk1/S1P/SIRT1 axis may be a novel therapeutic strategy for the treatment of leukemia.

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AML1–ETO promotes SIRT1 expression to enhance leukemogenesis of t(8;21) acute myeloid leukemia

Cited by 12 publications

References 27 publications

Methylation-associated silencing of BASP1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Methylation-associated silencing of BASP1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

The RUNX1–ETO fusion protein trans‐activates c‐KIT expression by recruiting histone acetyltransferase P300 on its promoter

Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling

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