GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death

Silva, Juliana Alves da; Carvalho, Juliana Lott; Rabello, Doralina do Amaral; Serejo, Teresa Raquel Tavares; Rego, Eduardo Magalhães; Neves, Francisco Assis Rocha; Lucena-Araújo, Antonio R.; Silva, Fábio Pittella; Saldanha-Araújo, Felipe

doi:10.1007/s10637-018-0613-x

Cited by 10 publications

(5 citation statements)

References 26 publications

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“…G9a is upregulated in hematological malignancies, for which G9a inhibitors have been identified as promising targets for patient management ( Table 3 ) [ 154 , 155 , 156 , 157 , 158 ]. In T-lymphoblastic leukemia cells (T-ALL), inhibiting G9a activity suppresses cellular proliferation and induces apoptosis by downregulating the expression of Bcl-2 and upregulating the expression of Bax and caspase-3 [ 155 ].…”

Section: G9a In Cancermentioning

confidence: 99%

“…In T-lymphoblastic leukemia cells (T-ALL), inhibiting G9a activity suppresses cellular proliferation and induces apoptosis by downregulating the expression of Bcl-2 and upregulating the expression of Bax and caspase-3 [ 155 ]. Likewise, in chronic lymphocytic leukemia, targeting G9a and GLP was shown to stimulate cancer cell death [ 154 ]. In multiple myeloma, G9a fosters ReIB-dependent cancer growth and survival, whereas its depletion reduces the expression of ReIB and increases the expression of pro-apoptotic genes, such as Bim and BMF [ 118 ].…”

Section: G9a In Cancermentioning

confidence: 99%

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Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Poulard

Noureddine

Pruvost

et al. 2021

Life

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G9a is a lysine methyltransferase catalyzing the majority of histone H3 mono- and dimethylation at Lys-9 (H3K9), responsible for transcriptional repression events in euchromatin. G9a has been shown to methylate various lysine residues of non-histone proteins and acts as a coactivator for several transcription factors. This review will provide an overview of the structural features of G9a and its paralog called G9a-like protein (GLP), explore the biochemical features of G9a, and describe its post-translational modifications and the specific inhibitors available to target its catalytic activity. Aside from its role on histone substrates, the review will highlight some non-histone targets of G9a, in order gain insight into their role in specific cellular mechanisms. Indeed, G9a was largely described to be involved in embryonic development, hypoxia, and DNA repair. Finally, the involvement of G9a in cancer biology will be presented.

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Section: G9a In Cancermentioning

confidence: 99%

Section: G9a In Cancermentioning

confidence: 99%

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Poulard

Noureddine

Pruvost

et al. 2021

Life

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“…Among those, EHMT2 and COPS7A are promising CLL risk gene candidates. The heterodimeric methyltransferases EHMT1 and EHMT2 have recently been implicated with prognosis of CLL and CLL cell viability(33). COPS7A (previous name COP9) is involved in the Transcription-Coupled Nucleotide Excision Repair (TC-NER) pathway and the COP9 signalosome complex (CSN) is involved in phosphorylation of p53/TP53, JUN, I-kappa-B-alpha/NFKBIA, ITPK1 and IRF8/ICSBP.…”

Section: Resultsmentioning

confidence: 99%

Efficient and Flexible Integration of Variant Characteristics in Rare Variant Association Studies Using Integrated Nested Laplace Approximation

Sušak

Serra

Rabionet

et al. 2020

Preprint

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28 Rare variants are thought to play an important role in the etiology of complex diseases and may 29 explain a significant fraction of the missing heritability in genetic disease studies. Next-30 generation sequencing facilitates the association of rare variants in coding or regulatory regions 31 with complex diseases in large cohorts at genome-wide scale. However, rare variant association 32 studies (RVAS) still lack power when cohorts are small to medium-sized and if genetic variation 33 explains a small fraction of phenotypic variance. Here we present a novel Bayesian rare variant 34 Association Test using Integrated Nested Laplace Approximation (BATI). Unlike existing RVAS 35 tests, BATI allows integration of individual or variant-specific features as covariates, while 36 efficiently performing inference based on full model estimation. We demonstrate that BATI 37 outperforms established RVAS methods on realistic, semi-synthetic whole-exome sequencing 38 cohorts, especially when using meaningful biological context, such as functional annotation. We 39 show that BATI achieves power above 75% in scenarios in which competing tests fail to identify 40 risk genes, e.g. when risk variants in sum explain less than 0.5% of phenotypic variance. We 41 have integrated BATI, together with five existing RVAS tests in the 'Rare Variant Genome Wide 42 Association Study' (rvGWAS) framework for data analyzed by whole-exome or whole genome 43 sequencing. rvGWAS supports rare variant association for genes or any other biological unit 44 such as promoters, while allowing the analysis of essential functionalities like quality control or 45 filtering. Applying rvGWAS to a Chronic Lymphocytic Leukemia study we identified eight 46 candidate predisposition genes, including EHMT2 and COPS7A.47 Data availability and implementation 48 All relevant data are within the manuscript and pipeline implementation on49 https://github.com/hanasusak/rvGWAS 3 50 Author summary 51 Complex diseases are characterized by being related to genetic factors and environmental52 factors such as air pollution, diet etc. that together define the susceptibility of each individual to 53 develop a given disease. Much effort has been applied to advance the knowledge of the genetic 54 bases of such diseases, specially in the discovery of frequent genetic variants in the population 55 increasing disease risk. However, these variants usually explain a little part of the etiology of 56 such diseases. Previous studies have shown that rare variants, i.e. variants present in less than 57 1% of the population, may explain the rest of the variability related to genetic aspects of the 58 disease.59 Genome sequencing offers the opportunity to discover rare variants, but powerful statistical 60 methods are needed to discriminate those variants that induce susceptibility to the disease. 61 Here we have developed a powerful and flexible statistical approach for the detection of rare 62 variants associated with a disease and we have integrated it into a computer tool that is eas...

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“…G9a and GLP seem to play a critical role in several hematological malignancies such as multiple myeloma (MM) [ 76 ] and both myelocytic [ 77 – 79 ] and lymphocytic leukemias [ 80 , 81 ] (Fig. 3 ).…”

Section: Oncogenic Functions Of Glp and G9a In Lymphoid Neoplasmsmentioning

confidence: 99%

“…Our group identified overexpression of GLP in samples from CLL patients, and its aberrant expression was associated with a poor prognosis. Additionally, we observed that G9a/GLP pharmacological inhibition markedly induced cell death in CLL cells, demonstrating the role of these methyltransferases as potential targets for treatment and progression control of CLL [ 80 ].…”

Section: Chronic Lymphoblastic Leukemiamentioning

confidence: 99%

GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms

Silva-Carvalho,

Filiú-Braga,

Bogéa

et al. 2024

Cancer Cell Int

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Histone methyltransferases (HMTs) are enzymes that regulate histone methylation and play an important role in controlling transcription by altering the chromatin structure. Aberrant activation of HMTs has been widely reported in certain types of neoplastic cells. Among them, G9a/EHMT2 and GLP/EHMT1 are crucial for H3K9 methylation, and their dysregulation has been associated with tumor initiation and progression in different types of cancer. More recently, it has been shown that G9a and GLP appear to play a critical role in several lymphoid hematologic malignancies. Importantly, the key roles played by both enzymes in various diseases made them attractive targets for drug development. In fact, in recent years, several groups have tried to develop small molecule inhibitors targeting their epigenetic activities as potential anticancer therapeutic tools. In this review, we discuss the physiological role of GLP and G9a, their oncogenic functions in hematologic malignancies of the lymphoid lineage, and the therapeutic potential of epigenetic drugs targeting G9a/GLP for cancer treatment.

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GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death

Cited by 10 publications

References 26 publications

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Efficient and Flexible Integration of Variant Characteristics in Rare Variant Association Studies Using Integrated Nested Laplace Approximation

GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms

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