Simona Jurković Mlakar

University of Geneva

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Marc Ansari

University of Geneva

Janja Marc

University of Ljubljana

Vid Mlakar

University of Geneva

Tiago Nava

Centre Hospitalier Universitaire Sainte-Justine

Maja Krajinović

Université de Montréal

Janez Preželj

Ljubljana University Medical Centre

Henrique Bittencourt

Centre Hospitalier Universitaire Sainte-Justine

Chakradhara Rao S. Uppugunduri

University of Geneva

Joško Osredkar

Ljubljana University Medical Centre

Jaap Jan Boelens

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

University of Geneva

University of Ljubljana

Ljubljana University Medical Centre

Jožef Stefan Institute

Centre Hospitalier Universitaire Sainte-Justine

University Hospital of Geneva

Karolinska Institutet

Université de Montréal

University College London

University of Rijeka

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A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma

Journal of Experimental & Clinical Cancer Research (2021)

Vid Mlakar Edouard Morel Simona Jurković Mlakar Marc Ansari Fabienne Gumy‐Pause

Abstract Neuroblastoma is the most common extra-cranial solid tumor in children, representing approximately 8% of all malignant childhood tumors and 15% of pediatric cancer-related deaths. Recent sequencing and transcriptomics studies have demonstrated the RAS-MAPK pathway’s contribution to the development and progression of neuroblastoma. This review compiles up-to-date evidence of this pathway’s involvement in neuroblastoma. We discuss the RAS-MAPK pathway’s general functioning, the clinical implications of its deregulation in neuroblastoma, and current promising therapeutics targeting proteins involved in signaling.

Childhood Cancer

10.1186/s13046-021-01967-x

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Citations (38)

Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT

Bone Marrow Transplantation (2021)

Marc Ansari Kateryna Petrykey Mohamed Aziz Rezgui Veronica Del Vecchio Jacques Cortyl

Genetic predisposition

10.1038/s41409-021-01386-8

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GSTM1 and GSTT1 Double Null Genotypes Determining Cell Fate and Proliferation as Potential Risk Factors of Relapse in Children With Hematological Malignancies After Stem Cell Transplantation. On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation

Research Square (Research Square) (2021)

Simona Jurković Mlakar Chakradhara Rao Uppugunduri Satyanarayana Tiago Nava Vid Mlakar Hadrien G. Golay

Abstract BackgroundRelapse is the major cause of treatment failure in children with hematological malignancies (HMs) undergoing busulfan (BU)- based allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferases (GSTs) isoforms that participate in BU detoxification and protect cells against stress and cell death may be linked to post-HSCT outcomes. This study aimed to retrospectively evaluate the genetic association of null variants of Glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with HMs undergoing BU- containing allogeneic HSCT and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST -gene edited cell models.Methods GSTM1- and GSTT1- null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1- null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell-death studies were conducted in GSTs - null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. Results Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76 - 15.42; p= 1.9 x 10 -5 ]). BU induced cell death preferentially in THP1 GSTM1(non-null) and LCLs GSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. ConclusionThe clinical association suggests that GSTM1 / GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation. Trial registrationClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.

Null allele

10.21203/rs.3.rs-439729/v1

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ADRA2A is involved in neuro‐endocrine regulation of bone resorption

Journal of Cellular and Molecular Medicine (2015)

Vid Mlakar Simona Jurković Mlakar Janja Zupan Radko Komadina Janez Preželj

Abstract Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2‐adrenergic receptor ( AR ), but there are conflicting evidence on presence and role of α2A‐ AR in bone. The aim of this study was to investigate the presence of α2A‐ AR and its involvement in neuro‐endocrine signalling of bone remodelling in humans. Real‐time polymerase chain reaction ( PCR ) and immunohistochemistry were used to investigate α2A‐ AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNP s located in α2A‐ AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real‐time PCR , genetic association study between rs553668 A>G and rs1800544 C>G SNP s and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A‐ AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A‐ AR mRNA level in human bone samples through the stability of mRNA . α2A‐ AR gene locus associates with important bone remodelling markers ( BMD , CTX , Cathepsin K and pOC ). The results of this study are providing comprehensive new evidence that α2A‐ AR is involved in neuro‐endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNP s in α2A‐ AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis.

Bone remodeling

Cathepsin K

SNP

10.1111/jcmm.12505

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The Catalytic Activity of GSTM1 In vitro is Independent of MAPK8

Drug Metabolism Letters (2021)

Shannon Robin Khalil Ben Hassine Simona Jurković Mlakar Vid Mlakar Marc Ansari

Background: Glutathione S-transferases (GSTs) are phase II metabolic enzymes crucial for the metabolism of electrophilic drugs. Additionally, several GST isoforms are involved in protein- protein interaction with mitogen-activated protein kinases (MAPKs), modulating apoptosis pathways. Methods: To assess the potential change of enzymatic activity, we performed a GST enzyme assay with human recombinant GSTM1 in the presence and absence of MAPK8. Recently, GSTM1 has been demonstrated to interact with MAPK8 both in silico and in vitro. The binding interface predicted in silico comprised amino acid residues present on the surface of the protein and a few were deep in the active site of the protein. Results: The experiment demonstrated that the GSTM1 activity was conserved even in the presence of MAPK8 in the assay. Conclusion: The possible alteration in the activity of MAPK8 in this interaction needs to be evaluated in further experiments.

Glutathione S-transferase

10.2174/1872312814666211122164456

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Opposite Effects ofGSTM1– andGSTT1– Gene Deletion Variants on Bone Mineral Density

Disease Markers (2011)

Simona Jurković Mlakar Joško Osredkar Janez Preželj Janja Marc

Oxidative stress is associated with osteoporosis. The glutathione S-transferases form the major detoxifying group of enzymes responsible for eliminating products of oxidative stress. We have therefore proposed GSTM1 and GSTT1 genes as candidates for studying the genetics of osteoporosis. The aim of the present study was to examine possible association of GSTM1 and GSTT1 gene deletion polymorphisms, alone or in combination, with bone mineral density at femoral neck (BMD_fn), lumbar spine (BMD_ls) and total hip (BMD_th) in Slovenian elderly women and men. GSTM1 and GSTT1 gene deletion polymorphisms in 712 elderly people were analyzed using the triplex PCR method for the presence of GSTM1 and GSTT1 gene segments. BMD_fn, BMD_ls and BMD_th were measured by the dual-energy X-ray absorptiometry (DEXA) method. Results were analyzed using univariate statistic model adjusted for sex, body mass index (BMI) and age. Our results showed the significant differences in BMD_th, BMD_ls and BMD_fn values ( p = 0.031, 0.017 and 0.023, respectively) in subgroups of GSTT1 gene deletion polymorphism. For GSTM1 gene deletion polymorphism borderline significant association was found with BMD_ls ( p = 0.100). Furthermore, subjects with homozygous deletion of GSTT1 gene showed higher BMD values on all measured skeletal sites and, in contrast, subjects with homozygous deletion of GSTM1 gene showed lower BMD values. Moreover, a gene-gene interaction study showed significant association of GSTM1 -null and GSTT1 -null polymorphisms with BMD_ls values ( p = 0.044). Carriers with a combination of the presence of GSTT1 gene and the homozygous absence of GSTM1 gene fragment were associated with the lower BMD values at all skeletal sites. The significant association of combination of GSTT1 gene presence and homozygous absence of GSTM1 gene with BMD was demonstrated, suggesting that it could be used, if validated in other studies, as genetic marker for low BMD.

Gene polymorphism

10.1155/2011/521597

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GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation

Journal of Cancer Research and Clinical Oncology (2021)

Simona Jurković Mlakar Chakradhara Rao S. Uppugunduri Tiago Nava Vid Mlakar Hadrien G. Golay

This study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models.GSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines.Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76-15.42; p = 1.9 × 10-5]). BU-induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation.The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation.

Hematology

Null cell

Null allele

10.1007/s00432-021-03769-2

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Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation

The Pharmacogenomics Journal (2021)

Chakradhara Rao S. Uppugunduri Patricia Huezo-Diaz Tiago Nava Mohamed Aziz Rezgui Vid Mlakar

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Cumulative incidence

10.1038/s41397-021-00251-7

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11q deletion in neuroblastoma: a review of biological and clinical implications

Molecular Cancer (2017)

Vid Mlakar Simona Jurković Mlakar Gonzalo López John M. Maris Marc Ansari

Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.

Gene deletion

10.1186/s12943-017-0686-8

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Citations (127)

Testing GSTP1 genotypes and haplotypes interactions in Slovenian post-/pre-menopausal women: Novel involvement of glutathione S-transferases in bone remodeling process

Maturitas (2012)

Simona Jurković Mlakar Janez Preželj Janja Marc

GSTP1

Bone remodeling

10.1016/j.maturitas.2011.11.023

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Citations (12)