Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells

Spagnuolo, Manuela; Regazzo, Giulia; Dominici, Marco De; Sacconi, Andrea; Pelosi, Andrea; Korita, Etleva; Marchesi, Francesco; Pisani, Francesco; Magenta, Alessandra; Lulli, Valentina; Cordone, Iole; Mengarelli, Andrea; Strano, Sabrina; Blandino, Giovanni; Rizzo, Maria Giulia; Calabretta, Bruno

doi:10.3324/haematol.2018.191213

Cited by 19 publications

(12 citation statements)

References 48 publications

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“…The canonical Wnt/β-catenin pathway is activated when the Wnt ligand binds to the Frizzled (FZD) receptor and its co-receptor from the low-density lipoprotein receptor-related protein 5/6 class (LRP5/6) (MacDonald et al, 2009). Previous studies have demonstrated that the miR-17-92 cluster could regulate Wnt signaling via directly targeting Wnt pathway components, such as FZD4 and LRP6 (Landskroner-Eiger et al, 2015) or the Wnt signaling inhibitors FRZB and HIPK1 (Wu et al, 2013; Spagnuolo et al, 2019). In addition, the miR-17-92 cluster could inhibit Wnt signaling via targeting E2F1.…”

Section: Discussionmentioning

confidence: 99%

“…To date, a number of other transcription factors have been identified as direct regulators of MIR17HG transcription. Among the identified regulators, c-Myc, N-Myc, STAT3, STAT5, MYCN, MYB, Spi-1, Fli-1, Pim-1, cyclin D1, AML1, ETS1, ETS2, NKX3.1, and E2F family members activate (Fontana et al, 2007; Sylvestre et al, 2007; Yu et al, 2008; De Brouwer et al, 2012; Feuermann et al, 2012; Kayali et al, 2012; Thomas et al, 2013; Kabbout et al, 2014; Yang et al, 2015; Spagnuolo et al, 2019), whereas p53 and C/EBPβ suppress the transcription of MIR17HG (Yan et al, 2009; Yan et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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The Wnt/β-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster

Huang

Xing

et al. 2019

Front. Genet.

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The miR-17-92 cluster is involved in animal development and homeostasis, and its dysregulation leads to human diseases such as cancer. In the present study, we investigated the functional link between miR-17-92 cluster and Wnt/β-catenin signaling pathway in ICP2 and DF1 cells. We demonstrated that ectopic expression of either LEF1 or β-catenin increased the promoter activity of the miR-17-92 cluster host gene (MIR17HG) and combined ectopic expression of LEF1 and β-catenin further enhanced the promoter activity; while knockdown of either LEF1 or β-catenin reduced the MIR17HG promoter activity. Both LEF1 and β-catenin could directly bind to the MIR17HG promoter. Furthermore, we demonstrated that low doses of lithium chloride (LiCl), an activator of Wnt/β-catenin signaling pathway, increased MIR17HG promoter activity and the endogenous expression of the miR-17-92 cluster, while high doses of LiCl had the opposite effects. Treatment with XAV-939, an inactivator of the Wnt/β-catenin pathway, reduced the endogenous expression of miR-17-92 cluster. Finally, we found that low doses of LiCl promoted the proliferation of ICP2 and DF1 cells, while high doses of LiCl inhibited the proliferation of ICP2 and DF1 cells. Taken together, our results reveal that MIR17HG is a target of LEF1 and the Wnt/β-catenin pathway and suggest that the miR-17-92 cluster may, at least in part, mediate the proliferation-promoting effect of the Wnt/β-catenin pathway in cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Wnt/β-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster

Huang

Xing

et al. 2019

Front. Genet.

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“…Several transcription factors with a role in differentiation and proliferation control, have been found to transcriptionally activate miR-17-92, such as RUNX1, EGR2, p53, FLI1 and MYC 47,[63][64][65] (also see 66 ). Transcriptional activation of the miR-17-92 cluster by the transcription factor MYB is implicated in the growth-promoting effects of MYB in Ph-positive leukemia cells 67 . This direct activation of miR-17-92 by MYB was also observed in K562 cells.…”

Section: Tal1 and Mir-17-92 In Differentiationmentioning

confidence: 99%

The transcription factor TAL1 and miR-17-92 create a regulatory loop in hematopoiesis

Meyer

Herkt

Kunze‐Schumacher

et al. 2020

Sci Rep

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A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain gene expression patterns during hematopoiesis. In this network, transcription factors regulate each other and are involved in regulatory loops with microRNAs. The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.

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“…Previous studies indicated that MYB transcription is mainly regulated through a transcriptional attenuation site within the first intron 14 , 15 . miRNAs including miR-150 and miR-17-92 can target MYB mRNA in a stage-specific manner 16 , 17 . PU.1 negatively regulates the c-myb promoter during granulocytic differentiation 18 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of MYB by distal enhancer elements in human myeloid leukemia

Jiang

Cheng

et al. 2021

Cell Death Dis

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MYB plays vital roles in regulating proliferation and differentiation of hematopoietic progenitor cells, dysregulation of MYB has been implicated in the pathogenesis of leukemia. Although the transcription of MYB has been well studied, its detailed underlying regulatory mechanisms still remain elusive. Here, we detected the long-range interaction between the upstream regions, −34k and −88k, and the MYB promoter in K562, U937, and HL-60 cells using circularized chromosome conformation capture (4C) assay, which declined when MYB was downregulated during chemical-induced differentiation. The enrichment of enhancer markers, H3K4me1 and H3K27ac, and enhancer activity at the −34k and −88k regions were confirmed by ChIP-qPCR and luciferase assay respectively. ChIP-qPCR showed the dynamic binding of GATA1, TAL1, and CCAAT/enhancer-binding protein (C/EBPβ) at −34k and −88k during differentiation of K562 cells. Epigenome editing by a CRISPR-Cas9-based method showed that H3K27ac at −34k enhanced TF binding and MYB expression, while DNA methylation inhibited MYB expression. Taken together, our data revealed that enhancer elements at −34k are required for MYB expression, TF binding, and epigenetic modification are closely involved in this process in human myeloid leukemia cells.

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Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells

Cited by 19 publications

References 48 publications

The Wnt/β-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster

The Wnt/β-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster

The transcription factor TAL1 and miR-17-92 create a regulatory loop in hematopoiesis

Regulation of MYB by distal enhancer elements in human myeloid leukemia

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