Micro-ribonucleic acid-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia

Schneider, Edith; Staffas, Anna; Röhner, Linda; Malmberg, Erik Delsing; Ashouri, Arghavan; Krowiorz, Kathrin; Pochert, Nicole; Miller, Christina; Wei, Stella Yuan; Arabanian, Laleh S.; Buske, Christian; Döhner, Hartmut; Bullinger, Lars; Fogelstrand, Linda; Heuser, Michael; Döhner, Konstanze; Xiang, Peng; Rüschmann, Jens; Petriv, Oleh I.; Heravi-Moussavi, Alireza; Hansen, Carl L.; Hirst, Martin; Humphries, R. Keith; Rouhi, A. Maureen; Palmqvist, Lars; Kuchenbauer, Florian

doi:10.3324/haematol.2017.177485

Cited by 8 publications

(5 citation statements)

References 53 publications

(76 reference statements)

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“…Given a previous study indicating MEIS1 upregulation of FLI1 in normal hematopoiesis [ 29 ], we hypothesised that a positive feedback loop may exist between FLI1 and MEIS1 in AML. Since MEIS1 levels are frequently elevated in normal karyotype AML (CN-AML), we used the murine Hoxa9/Meis1 AML model as a surrogate for CN-AML and performed Meis1 ChIP-seq analysis where we overexpressed HA-tagged wildtype Meis1 or an HA-tagged DNA binding mutant Meis1 (deltaHD-Meis1) with Hoxa9 [ 21 , 30 ]. We looked for Meis1 binding sites enriched in Hoxa9/Meis1 that were absent or less enriched for deltaHD-Meis1 binding in Hoxa9/deltaHD-Meis1.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the importance and regulation of key enhancers for human MEIS1 expression

et al. 2022

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Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.

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Section: Resultsmentioning

confidence: 99%

Elucidating the importance and regulation of key enhancers for human MEIS1 expression

et al. 2022

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“…HOXA9 gene expression pattern has been investigated in AML [22]. Yet, there is still a lack of evidence concerning its association with MEIS1 gene expression [23].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the HOXA9 and MEIS1 genes as a potential biomarker in adult acute myeloid leukemia

Abdelrahman

Tolba

Kamal

et al. 2023

Egypt J Med Hum Genet

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Background Acute myeloid leukemia (AML) is a heterogeneous disorder encompassing a set of hematopoietic tumors that develop when the myeloid precursor cells undergo disproportionate clonal proliferation. Homeobox A 9 (HOXA9) is a pioneer transcription factor in AML pathogenesis along with its cofactor myeloid ecotropic integration site 1 (MEIS1). Our work aimed to evaluate the different expression levels of HOXA9 and MEIS1 genes and their diagnostic and prognostic significance in adult Egyptian patients with de novo AML. The study was carried out on 91 de novo AML Egyptian patients and 41 healthy individuals. Bone marrow samples were obtained from both patients and controls and then tested by reverse transcription-quantitative polymerase chain reaction to assess the mRNA expression in the studied genes. Results HOXA9 and MEIS1 gene expression levels were significantly elevated in AML patients compared to controls (p < 0.001). There was a statistically significant positive correlation between HOXA9 and MEIS1 gene expression in AML patients. However, there was no association between HOXA9 and MEIS1 gene expression levels and disease-free survival (DFS) and overall survival (OS) (p = 0.264 and 0.351, respectively). Conclusion HOXA9 and MEIS1 genes are highly expressed in Egyptian AML patients, suggesting their interesting pathogenic role in AML. They could be used as markers for the diagnosis of AML, but not for the disease prognosis.

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“…A number of studies have reported that miR-155 can act as an accelerator to promote the development of acute. [9][10][11] In addition to blood diseases, miR-155 is also closely related to the development of solid tumors. The study found that miR-155 plays a key role in promoting the progression of glioma and can be a prognostic factor for the survival of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, miR-155 is also closely related to tumors. [9][10][11][12][13][14][15] Especially, it has been found that miR-155 is upregulated in the liver tissues of patients. [16][17][18] So far, the role of miR-155 in the development of human liver cancer has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

miR-155 Accelerates the Growth of Human Liver Cancer Cells by Activating CDK2 via Targeting H3F3A

Xin

Xie

et al. 2020

Molecular Therapy - Oncolytics

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miR-155 is associated with the promotion of tumorigenesis. Herein, we indicate that abnormal miR-155 was negatively correlated with the expression of P21WAF1/Cip1. Our results suggest that miR-155 alters the transcriptome and inhibits the expression of H3F3A in liver cancer cells. Therefore, miR-155 inhibits the methylation modification of histone H3 on the 27 th lysine. Notably, on the one hand, miR-155-dependent CTCF loops cause the CDK2 interacting with cyclin E in liver cancer cells; on the other hand, miR-155 promotes the phosphorylation modification of CDK2 by inhibiting H3F3A. Subsequently, miR-155 competitively blocks the binding of RNA polymerase II (RNA Pol II) to the P21WAF1/CIP1 promoter by increasing the phosphorylation of CDK2, inhibiting the transcription and translation of P21WAF1/CIP1. Strikingly, excessive P21WAF1/CIP1 abolishes the cancerous function of miR-155. In conclusion, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation.

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Micro-ribonucleic acid-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia

Cited by 8 publications

References 53 publications

Elucidating the importance and regulation of key enhancers for human MEIS1 expression

Elucidating the importance and regulation of key enhancers for human MEIS1 expression

Evaluation of the HOXA9 and MEIS1 genes as a potential biomarker in adult acute myeloid leukemia

miR-155 Accelerates the Growth of Human Liver Cancer Cells by Activating CDK2 via Targeting H3F3A

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