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1. Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer

Author

Vanessa Ortiz-Barahona, Marta Soler, Veronica Davalos, Carlos A. García-Prieto, Maxime Janin, Fernando Setien, Irene Fernández-Rebollo, Joan J. Bech-Serra, Carolina De La Torre, Sonia Guil, Alberto Villanueva, Pei-Hong Zhang, Li Yang, Marco Guarnacci, Ulrike Schumann, Thomas Preiss, Ugne Balaseviciute, Robert Montal, Josep M. Llovet, and Manel Esteller

Subjects
RNA modifications, 5-methylcytosine RNA methyltransferase, NSUN7, Epigenetics, DNA methylation, Liver cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.

Published
2023
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2. Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

Author

Maxime Janin, Laia Coll-SanMartin, and Manel Esteller

Subjects
Ribosomal RNA, Transfer RNA, Translation, Human cancer, Epitranscriptomics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.

Published
2020
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3. Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression

Author

Maxime Janin and Manel Esteller

Subjects
General Medicine
Abstract

Summary: Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., p. 228 (8) .

Published
2023
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5. Data from In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Author

Bertrand Tavitian, Judith Favier, Anne-Paule Gimenez-Roqueplo, Laure Fournier, Philippe Halimi, Pierre Rustin, Paule Benit, Charles-André Cuenod, Sébastien Fontaine, Benjamin Banting, Estelle Robidel, Nelly Burnichon, Gwennhael Autret, Franck Zinzindohoué, Chris Ottolenghi, Maxime Janin, Laurence Amar, Alexandre Buffet, Aurélie Morin, Alexandre Bellucci, and Charlotte Lussey-Lepoutre

Abstract

Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy.Experimental Design: A pulsed proton magnetic resonance spectroscopy (1H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb−/− or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors.Results: A succinate peak was observed at 2.44 ppm by 1H-MRS in all Sdhb−/−-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene.Conclusions: Detection of succinate by 1H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. ©2015 AACR.

Published
2023
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6. Supplementary data from In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Author

Bertrand Tavitian, Judith Favier, Anne-Paule Gimenez-Roqueplo, Laure Fournier, Philippe Halimi, Pierre Rustin, Paule Benit, Charles-André Cuenod, Sébastien Fontaine, Benjamin Banting, Estelle Robidel, Nelly Burnichon, Gwennhael Autret, Franck Zinzindohoué, Chris Ottolenghi, Maxime Janin, Laurence Amar, Alexandre Buffet, Aurélie Morin, Alexandre Bellucci, and Charlotte Lussey-Lepoutre

Abstract

Figure S1- Phantom spectra of succinate at 4.7T and 3 T. Figure S2- SUCCES in Sdhb-/- allografted tumors in mice. Figure S3 - SUCCES in SDHx-mutated PPGL. Figure S4 - SUCCES in non SDHx-mutated PPGL.

Published
2023
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7. Epigenetic Awakening of Viral Mimicry in Cancer

Author

Manel Esteller and Maxime Janin

Subjects
Epigenomics, 0301 basic medicine, Methyltransferase, macromolecular substances, Epigenesis, Genetic, Histones, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Humans, Enhancer of Zeste Homolog 2 Protein, Epigenetics, biology, EZH2, Cancer, DNA Methylation, medicine.disease, 030104 developmental biology, Histone, Oncology, 030220 oncology & carcinogenesis, DNA methylation, biology.protein, Cancer research, DNA hypomethylation
Abstract

Summary: In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation. See related article by Deblois et al., p. 1312.

Published
2020
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8. Abstract 153: Epigenetic loss of NSUN5 in glioma drives a global protein synthesis depletion along with the emergence of a stress adaptive translational program

Author

Vanessa Ortiz Barahona, Maxime Janin, and Manel Esteller

Subjects
Stress (mechanics), Cancer Research, Oncology, Glioma, medicine, Protein biosynthesis, Epigenetics, Biology, medicine.disease, Cell biology
Abstract

One of the known hallmarks of cancer is an aberrant RNA transcriptome, and yet, it cannot always be fully due to genetic or epigenetic alterations at the transcriptional start sites of the genes. Indeed, recent evidences point out to new malignant alterations at the RNA level itself. RNA molecules have been found to show more than 100 differently chemically modified nucleotides, and such post-transcriptional modifications play a role in controlling RNA homeostasis, being all grouped under the term ‘epitranscriptome'. In our study, we reported that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate 5-methylcytosine RNA methyltransferase. As NSUN5 activity has not been formally described in human cells yet, we studied its potential targets in the human transcriptome, demonstrating its role in the methylation of the cytosine 3782 in the 28S ribosomal RNA (rRNA). Logically, we found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA, and this depletion drives an overall depletion of protein synthesis under stress conditions, analyzed by O-propargyl-puromycin (OP-Puro) and [3H] leucine incorporation into nascent proteins. However, together with the depletion of global protein synthesis, we observed the emergence of an adaptive translational program for survival under conditions of cellular stress, assessed by combining three NGS-experiments: RNA-seq, Ribo-seq and SILAC. Moreover, as one of the genes increasing its expression upon NSUN5 silencing is the stress-related enzyme NQO1, we found out that NSUN5-depleted gliomas are sensitive to bioactivatable substrates of the NQO1 enzyme. Most importantly, we observed that NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival, conferring it value as a predictor of better patient outcome for this otherwise devastating disease. Citation Format: Vanessa Ortiz Barahona, Maxime Janin, Manel Esteller. Epigenetic loss of NSUN5 in glioma drives a global protein synthesis depletion along with the emergence of a stress adaptive translational program [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 153.

Published
2020
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9. Abstract 5416: Positioning the NQO1-bioactivatable drug isobutyl-deoxynyboquinone in diffuse intrinsic pontine glioma (DIPG): an exceptional therapeutic opportunity in pediatric brain tumor

Author

Carolina De La Torre, Pere Llinas Arias, Paul J. Hergenrother, Manel Esteller, Andres Morales La Madrid, Vanessa Ortiz Barahona, Maxime Janin, and Angel M. Carcaboso

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Cancer, medicine.disease, Pediatric cancer, Radiation therapy, Efficacy, Oncology, Cell culture, In vivo, Apoptosis, medicine, Transcriptional regulation, Cancer research, business
Abstract

Purpose: Diffuse Intrinsic Pontine Glioma (DIPG), is a very aggressive pediatric cancer with poor overall survival and no effective treatment. Despite numerous clinical trials, the overall survival remains at 9 months after diagnosis and only radiotherapy has shown a relative efficacy. Therefore, it is primordial to increase our understanding of the biology of DIPG tumors, as well as finding new healthcare strategies to tackle this pediatric disease. Recently, we discovered that NQO1, a stress-related protein, was overexpressed in 3 out of 6 DIPG patient-derived cell lines, as well as in half of the primary tissues. Interestingly, NQO1 overexpression can be targeted by substrates that induce an excessive oxidative stress into the cells that finally push them to apoptosis, while normal surrounding tissues with basal expression of NQO1 would be keep safe. Experimental procedure: This discovery prompted us to test in in vitro and in vivo assays a promising drug named isobutyl-deoxynyboquinone (IB-DNQ): a NQO1 bioactivatable substrate. We first tested the drug response of the 6 cell lines before testing it on orthotopic xenograft mouse models. We also investigated by which mechanism NQO1 is regulated in DIPG. Finally, we performed experiments in order to decipher by which mechanism NQO1 is regulated in DIPG. Results: We saw that NQO1 overexpressing cells are very sensitive to the drug, compared to the cell lines with normal expression. Moreover, we started to validate the use of IB-DNQ in vivo using a DIPG cell line treated or not (mock) with IB-DNQ and also a NQO1-knockdown model in orthotopic xenograft mice models, confirming that IB-DNQ crosses the blood brain barrier and increases the overall survival. NQO1 increased expression in DIPG is surprisingly not due to a NRF2-mediated transcriptional regulation as we did not observe a correlation between NQO1 transcript abundance and protein expression in DIPG cell lines, indicating that NRF2 pathway could not be implicated, but translational or post-translational regulation could be operating. We performed a polysome profiling of 4 patient-derived cell lines, a protein stability assay and a large scale proteome for the 6 cell lines (pending results). Conclusion: Our preliminary results, including drug efficacy, are very encouraging for the development of this new therapeutic in DIPG. This discovery represents a promising opportunity to tackle this devastating disease and a new hope for the patients and their families. Citation Format: Maxime Henri Janin, Vanessa Ortiz Barahona, Pere Llinas Arias, Carolina De La Torre, Angel Montero Carcaboso, Andres Morales La Madrid, Paul Hergenrother, Manel Esteller. Positioning the NQO1-bioactivatable drug isobutyl-deoxynyboquinone in diffuse intrinsic pontine glioma (DIPG): an exceptional therapeutic opportunity in pediatric brain tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5416.

Published
2020
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10. The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival

Author

Elise Saunier, Florence Habarou, Baharia Mograbi, Chantal Benelli, Odile Sergent, Marie-Thérèse Lavault, Paule Bénit, Laurence Huc, Morgane Fernier, Kévin Hardonnière, Chris Ottolenghi, Maxime Janin, Anthony Lemarié, Pierre Rustin, Samantha Antonio, Isabelle Gallais, Sylvie Bortoli, Cécile Héliès-Toussaint, Dominique Lagadic-Gossmann, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de Biochimie Métabolique, CHU Necker - Enfants Malades [AP-HP], Plateforme microscopie électronique, MRic Campus Santé, Rennes 1, France, French Ministry for Education and Research, Faculte des Sciences Pharmaceutiques et Biologiques de Rennes (University of Rennes 1), Region Provence Alpes Cote d'Azur, Agence regionale sante Provence Alpes Cote d'Azur, Direction regionale de l'Environnement, de l'amenagement et du logement Provence Alpes Cote d'Azur [6.3.3.3, 6.3.3.4], Universite Paris Descartes, Ligue contre le cancer [22,35,49,85], French National Academy of Medicine, ANR [ANR-13-CESA-0009], ITMO Cancer AVIESAN (National Alliance for Life Sciences and Health) within the framework of the Cancer Plan, Association for Cancer Research (ARC, CANC'AIR Genexposomic project), ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique(2013), Jonchère, Laurent, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique - - STEATOX2013 - ANR-13-CESA-0009 - CESA - VALID, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT ), Université Nice Sophia Antipolis - Faculté de Médecine ( UNS UFR Médecine ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR-13-CESA-0009,STEATOX,Impact des agents chimiques environnementaux sur les mécanismes de progression pathologique de la stéatose hépatique ( 2013 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
0301 basic medicine, Respiratory chain, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, atp synthase, oxidative stress, mitochondrial-function, Sodium-Hydrogen Exchanger 1, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, respiratory-chain, hepa1c1c7 cells, hexokinase-ii, Cellular Reprogramming, Warburg effect, 3. Good health, Cell biology, Liver, Benzo(a)pyrene, 030220 oncology & carcinogenesis, Epithelial-Mesenchymal Transition, Cell Survival, Cellular respiration, Citric Acid Cycle, kappa-b, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, [ SDV.EE.SANT ] Life Sciences [q-bio]/Ecology, environment/Health, 03 medical and health sciences, hepg2 cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Animals, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Lactic Acid, Carcinogen, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, complex ii, Epithelial Cells, Membrane hyperpolarization, apoptosis induction, Carcinogens, Environmental, Rats, 030104 developmental biology, chemistry, Apoptosis, Cancer cell, Energy Metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).

Published
2016
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11. In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Author

Estelle Robidel, Laure Fournier, Gwennhael Autret, Philippe Halimi, Paule Bénit, Sébastien Fontaine, Bertrand Tavitian, Alexandre Bellucci, Charlotte Lussey-Lepoutre, Maxime Janin, Chris Ottolenghi, Nelly Burnichon, Benjamin Banting, Judith Favier, Alexandre Buffet, Aurélie Morin, Franck Zinzindohoue, Anne-Paule Gimenez-Roqueplo, Laurence Amar, Charles-André Cuénod, Pierre Rustin, Tavitian, Bertrand, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine [Université Paris Diderot - Paris 7], Université Paris Diderot - Paris 7 (UPD7), This work received funding from the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégré sur le Cancer - SIRIC), the Agence Nationale de la Recherche (ANR-2011-JCJC-00701 MODEOMAPP), the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 259735, the Institut National du Cancer et la Direction Générale de l’Offre de Soins (INCa-DGOS_8663) for the COMETE network., Service d'hypertension artérielle et médecine vasculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie Métabolique, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de radiologie cardio-vasculaire [CHU HEGP], This work received funding from the Cancer Research for Personalized Medicine - CARPEMproject (Site de Recherche Intégré sur le Cancer- SIRIC), the Agence Nationale de la Recherche (ANR-2011-JCJC-00701MODEOMAPP), the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259735, the Institut National du Cancer et la Direction Générale de l'Offre de Soins (INCa-DGOS_8663) for the COMETE network., ANR-11-JSV1-0007,MODEOMAPP,Décryptage moléculaire de la malignité dans le phéochromocytome et paragangliome(2011), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-AP-HP Hôpital européen Georges-Pompidou (Paris), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR : ANR-2001-JCJC-00701-MODEOMAPP, Autret, Gwennhael, Jeunes Chercheuses et Jeunes Chercheurs - Décryptage moléculaire de la malignité dans le phéochromocytome et paragangliome - - MODEOMAPP2011 - ANR-11-JSV1-0007 - JCJC - VALID, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Hôpital Européen Georges Pompidou [APHP] (HEGP)

Subjects
0301 basic medicine, Male, Cancer Research, Pathology, medicine.medical_specialty, Succinate, SDHB, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Succinic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, Biology, medicine.disease_cause, Pheochromocytoma, 03 medical and health sciences, Mice, paraganglioma, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Paraganglioma, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, SDHA Gene Mutation, medicine, Animals, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Succinate dehydrogenase, Electron Transport Complex II, Membrane Proteins, imaging, medicine.disease, Xenograft Model Antitumor Assays, pheochromocytoma, magnetic resonance spectroscopy, 3. Good health, Succinate Dehydrogenase, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb−/− or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1H-MRS in all Sdhb−/−-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. ©2015 AACR.

Published
2016
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12. From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma

Author

Anne-Paule Gimenez-Roqueplo, Judith Favier, Paule Bénit, Chris Ottolenghi, Pierre Rustin, Charlotte Lepoutre-Lussey, Alexandre Buffet, Jan Trapman, Constance Thibault, Aurélie Morin, Luis Jaime Castro-Vega, Cécile Badoual, Maxime Janin, and Pathology

Subjects
0301 basic medicine, medicine.medical_specialty, SDHB, MAP Kinase Signaling System, Adrenal Gland Neoplasms, Computational biology, Pheochromocytoma, Neuroendocrine tumors, Biology, medicine.disease_cause, Biochemistry, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Animals, Humans, Molecular Biology, Mice, Knockout, Neurofibromin 1, Genetically engineered, medicine.disease, Succinate Dehydrogenase, 030104 developmental biology, 030220 oncology & carcinogenesis, Genetically Engineered Mouse, Knockout mouse, Mutation, Carcinogenesis
Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.

Published
2015

13. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia

Author

Marie Coutelier, Alexandre Dionne-Laporte, Marion Stoll, Alexandra Durr, Perrine Charles, Isabel Alonso, Maxime Jacoupy, Marion Gaussen, Paula Coutinho, Fanny Mochel, Garth A. Nicholson, Fanny Morice-Picard, Stephan Züchner, Giovanni Stevanin, Juliette Konop, Rebecca Schüle, Chris Ottolenghi, Florence Habarou, José Leal Loureiro, Cyril Goizet, Raphaël Matusiak, Alexis Brice, Maxime Janin, S. Sara Morais, Christel Depienne, Guy A. Rouleau, Marina L. Kennerson, Frédéric Darios, Mathilde Mairey, Chantal M. E. Tallaksen, Jean-Marie Saudubray, Feifei Tao, Christelle M. Durand, Patrick Calvas, Université Catholique de Louvain = Catholic University of Louvain (UCL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de Bordeaux Pellegrin [Bordeaux], Université de Bordeaux (UB), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal] (IBMC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), University of Miami [Coral Gables], John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia, Instituto de Investigação e Inovação em Saúde (I3S), Eberhard Karls University, CHU Toulouse [Toulouse], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro Hospitalar de Entre o Douro e Vouga, Hospital, McGill University, Centre d'infectiologie Necker-Pasteur [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], CARBILLET, Véronique, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto = University of Porto, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de biochimie métabolique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Ornithine, Candidate gene, Arginine, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Citrulline, Exome sequencing, Genetics, 0303 health sciences, Mutation, ALDH18A1, MESH: Middle Aged, delta-1-pyrroline-5-carboxylate synthase, genetics [Aldehyde Dehydrogenase], Middle Aged, Phenotype, 3. Good health, Pedigree, delta1-pyrroline-5-carboxylate synthase, human, MESH: Spastic Paraplegia, Hereditary / genetics, MESH: Young Adult, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, metabolism [Ornithine], Adult, Adolescent, Hereditary spastic paraplegia, MESH: Pedigree, metabolism [Arginine], Glutamic Acid, MESH: Ornithine / genetics, genetics [Mutation], MESH: Spastic Paraplegia, Hereditary / metabolism, Biology, MESH: Phenotype, MESH: Aldehyde Dehydrogenase / genetics, 03 medical and health sciences, Young Adult, genetics [Spastic Paraplegia, Hereditary], MESH: Arginine / metabolism, medicine, Humans, ddc:610, hereditary spastic paraplegia, 030304 developmental biology, MESH: Adolescent, genetics [Ornithine], MESH: Humans, Spastic Paraplegia, Hereditary, MESH: Mutation / genetics, MESH: Glutamic Acid / metabolism, metabolism [Glutamic Acid], MESH: Ornithine / metabolism, MESH: Adult, Original Articles, Aldehyde Dehydrogenase, medicine.disease, MESH: Male, chemistry, metabolism [Spastic Paraplegia, Hereditary], citrulline, ornithine, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.

Published
2015
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14. Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice

Author

Olivia Bawa, Paule Opolon, Olivier Bernard, Chris Ottolenghi, Muriel D. David, Virginie Penard-Lacronique, Maxime Janin, Elena Mylonas, S DeBotton, and Cyril Quivoron

Subjects
Cancer Research, Myeloid, Hematology, Biology, Hematopoietic Stem Cells, Molecular biology, Isocitrate Dehydrogenase, stomatognathic diseases, Mice, Isocitrate dehydrogenase, medicine.anatomical_structure, Retroviridae, Oncology, hemic and lymphatic diseases, Hematologic Neoplasms, Mutation (genetic algorithm), Mutation, medicine, Animals, Humans, Lymphoid neoplasms, Myeloid Cells, Lymphocytes, Cells, Cultured
Abstract

Isocitrate dehydrogenase ( IDH ) 2 R140Q mutation induces myeloid and lymphoid neoplasms in mice

Published
2014

15. Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group

Author

Denis Caillot, Sébastien Forget, Marie-Hélène Courtier, Aline Renneville, Olivier Bernard, Cécile Pautas, Hervé Dombret, Serge Koscielny, Daniel Rabier, Véronique Saada, Nathalie Auger, Claude Preudhomme, Jean-Baptiste Micol, Maxime Janin, Cyril Quivoron, Laurianne Scourzic, Elena Mylonas, Chris Ottolenghi, Edwige Leclercq, Robert Barouki, Annelise Bennaceur-Griscelli, Virginie Penard-Lacronique, Stéphane de Botton, Elisabeth Chachaty, Frank Griscelli, Céline Berthon, and Eric Solary

Subjects
Adult, Male, Cancer Research, NPM1, Myeloid, IDH1, Neoplasm, Residual, Kaplan-Meier Estimate, IDH2, Sensitivity and Specificity, Mass Spectrometry, Glutarates, Predictive Value of Tests, Biomarkers, Tumor, Medicine, Humans, WT1 Proteins, Aged, Acute leukemia, business.industry, Myeloid leukemia, Nuclear Proteins, Stereoisomerism, Middle Aged, medicine.disease, Prognosis, Molecular biology, Minimal residual disease, Isocitrate Dehydrogenase, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, ROC Curve, Area Under Curve, Immunology, Mutation, Female, France, business, Nucleophosmin
Abstract

Purpose Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). Patients and Methods Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. Results In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 μmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 μmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). Conclusion Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

Published
2013

16. Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group.

Author

Janin M, Mylonas E, Saada V, Micol JB, Renneville A, Quivoron C, Koscielny S, Scourzic L, Forget S, Pautas C, Caillot D, Preudhomme C, Dombret H, Berthon C, Barouki R, Rabier D, Auger N, Griscelli F, Chachaty E, Leclercq E, Courtier MH, Bennaceur-Griscelli A, Solary E, Bernard OA, Penard-Lacronique V, Ottolenghi C, and de Botton S

Subjects
Adult, Aged, Area Under Curve, Female, France, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Male, Mass Spectrometry, Middle Aged, Neoplasm, Residual blood, Nuclear Proteins blood, Nucleophosmin, Predictive Value of Tests, Prognosis, ROC Curve, Sensitivity and Specificity, Stereoisomerism, WT1 Proteins blood, Biomarkers, Tumor blood, Glutarates blood, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute diagnosis, Mutation
Abstract

Purpose: Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD)., Patients and Methods: Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy., Results: In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 μmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 μmol/L were associated with better overall (P = .008) and disease-free survival (P = .005)., Conclusion: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

Published
2014
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