EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia

Kosalai, Subazini Thankaswamy; Morsy, Mohammad Hamdy Abdelrazak; Papakonstantinou, Nikos; Mansouri, Larry; Stavroyianni, Niki; Kanduri, Chandrasekhar; Stamatopoulos, Kostas; Rosenquist, Richard; Kanduri, Meena

doi:10.1080/15592294.2019.1633867

Cited by 28 publications

(24 citation statements)

References 51 publications

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“…Secondly, PTEN plays critical roles in regulating not only hematopoietic stem cell activity through a Niche-dependent mechanism, but also hematopoiesis and leukemogenesis [341][342][343]. Furthermore, TAL1, c-Jun, EZH2, TRIM22, ETV6/RUNX1, miR-7, -22, -26b, -103, -125b, -126, -139-5p, -181c, -193a, -628, and -3142, as well as LncRNA HULC, UCA1, linc00239 and LINC00265 control leukemogenesis, proliferation, apoptosis or chemoresistance via PI3K/AKT pathway [344][345][346][347][348][349][350][351][352][353][354][355][356][357][358][359][360][361][362][363]. Hereafter, PI3K/AKT pathway inhibition is regarded as a therapeutic approach [364,365] followed by the preclinical studies in leukemia cells [366,367] in spite of the upregulated expression of P2RY14 in acute leukemia cells resistant to PI3K/ mTOR inhibition [368].…”

Section: (Nct01002248; Nct01476137; Nct00881946) (Tables 2 and 3)mentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

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Section: (Nct01002248; Nct01476137; Nct00881946) (Tables 2 and 3)mentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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“…Notably, EZH2 was recently shown to be capable to augment c-Myc transcriptional activity regardless of its methyl transferase activity. 22 In fact, analyzing public data (GSE115772 22 ) and datasets from the Open access and EZH2 that does not involve the methyltransferase activity of the latter one and which warrants further investigations.…”

Section: Notch-c-myc-facilitated Pd-l1 Induction Requires Ezh2mentioning

confidence: 99%

Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis

Bruns

Völkl

et al. 2021

J Immunother Cancer

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Emerging data suggest that CLL-cells efficiently evade immunosurveillance. T-cell deficiencies in CLL include immuno(metabolic) exhaustion that is achieved by inhibitory molecules, with programmed cell death 1/programmed cell death ligand 1 (PD-L1) signaling emerging as a major underlying mechanism. Moreover, CLL-cells are characterized by a close and recurrent interaction with their stromal niches in the bone marrow and lymph nodes. Here, they receive nurturing signals within a well-protected environment. We could previously show that the interaction of CLL-cells with stroma leads to c-Myc activation that is followed by metabolic adaptations. Recent data indicate that c-Myc also controls expression of the immune checkpoint molecule PD-L1. Therefore, we sought out to determine the role of stromal contact for the CLL-cells’ PD-L1 expression and thus their immuno-evasive phenotype.To do so, we analyzed PD-L1 expression on CLL cell (subsets) in untreated patients and on healthy donor-derived B-cells. Impact of stromal contact on PD-L1 expression on CLL-cells and the underlying signaling pathways were assessed in well-established in vitro niche models. Ex vivo and in vitro findings were validated in the Eµ-TCL1 transgenic CLL mouse model.We found increased PD-L1 expression on CLL-cells as compared with B-cells that was further enhanced in a cell-to-cell contact-dependent manner by stromal cells. In fact, circulating recent stromal-niche emigrants displayed higher PD-L1 levels than long-time circulating CLL-cells. Using our in vitro niche model, we show that a novel Notch-c-Myc-enhancer of zeste homolog 2 (EZH2) signaling axis controls PD-L1 upregulation. Ultimately, elevated PD-L1 levels conferred increased resistance towards activated autologous T-cells.In summary, our findings support the notion that the CLL microenvironment contributes to immune escape variants. In addition, several targetable molecules (eg, Notch or EZH2) could be exploited in view of improving immune responses in patients with CLL, which warrants further in-depth investigation.

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“…recruits MYC protein and binds to the IGF1R promoter to activate the transcription of IGF1R gene in a PRC2-independent manner, leading to the activation of its downstream PI3K/AKT signaling. 39 In adrenocortical carcinoma (ACC), EZH2 cooperates with transcription factor E2F1 to upregulate the expression of aggression-related genes, such as RRM2, PTTG1, and ASE1/PRC1, in a histone methyltransferaseindependent manner, thereby promoting the development of ACC. 40 Avni et al reported that polycomb proteins, such as YY1, Mel-18, Ring1A, EZH2, and EED, are recruited to the promoter of interleukin-4 (IL-4) and interferonγ (IFNγ), and induce the transcription of IL-4 and IFNγ cytokines in differentiated T helper cells.…”

Section: Ezh2 Act As Transcriptional Activator/ Coactivatormentioning

confidence: 99%

The noncanonical role of EZH2 in cancer

et al. 2021

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Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). Dysregulation of EZH2 causes alteration of gene expression and functions, thereby promoting cancer development. The regulatory function of EZH2 varies across different tumor types. The canonical role of EZH2 is gene silencing through catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3) in a PRC2‐dependent manner. Accumulating evidence indicates that EZH2 has an H3K27me3‐independent function as a transcriptional coactivator and plays a critical role in cancer initiation, development, and progression. In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.

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EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia

Cited by 28 publications

References 51 publications

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis

The noncanonical role of EZH2 in cancer

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