title: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.
abstract: Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Strullu
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guidez
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Service de Biologie Cellulaire, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Plateforme de Génétique Constitutionnelle-Nord (PfGC-Nord), Paris, France.|INSERM UMR 1137, Infection Antimicrobial Modelling and Evolution (IAME) Laboratory, Paris, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Service d'Hématologie Biologique, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Service d'Hématologie Biologique, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lainey
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Kazem
authors.initials: K
authors.lastname: Nouri
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Nakhaei-Rad
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Radovan
authors.initials: R
authors.lastname: Dvorsky
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lachenaud
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pereira
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Vivent
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Service de Biologie Cellulaire, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Verger
authors.affiliation: Equipe d'Accueil 7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Cochin, Service de Biochimie Génétique, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.affiliation: Assistance Publique des Hôpitaux de Marseille (AP-HM), Hôpital de la Timone, Service d'Hématologie Pédiatrique, Marseille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Galambrun
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades Paris, Centre d'Etudes des Déficits Immunitaires, Immuno-Hematology Unit, Paris, France.|Université Paris Descartes, Paris Sorbonne Cité, Paris, France.|INSERM UMR 1163, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service d'Hématologie Oncologie Pédiatrique, Paris, France.
authors.forename: Arnaud
authors.identifier: http://orcid.org/0000-0001-8363-1622
authors.initials: A
authors.lastname: Petit
authors.affiliation: Hôpital d'Enfants de Brabois, Service d'Onco-Hématologie Pédiatrique, Vandoeuvre lès Nancy, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Contet
authors.affiliation: Hôpital l'Archet, Service d'Onco-Hématologie Pédiatrique, Nice, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Poirée
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Montpellier, Service d'Onco-Hématologie Pédiatrique, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sirvent
authors.affiliation: CHU de Nantes, Service d'Onco-Hématologie Pédiatrique, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Méchinaud
authors.affiliation: CHU de Grenoble, Service d'Onco-Hématologie Pédiatrique, Grenoble, France.
authors.forename: Dalila
authors.initials: D
authors.lastname: Adjaoud
authors.affiliation: Hôpital de Hautepierre, Service de Pédiatrie, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paillard
authors.affiliation: CHU de Lille, Unité d'Hématologie Pédiatrique, Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nelken
authors.affiliation: Centre Hospitalier Félix Guyon, Saint-Denis, La Réunion, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Reguerre
authors.affiliation: Institut d'Hémato-Oncologie Pédiatrique (IHOP), Département d'Immunologie et Hématologie Pédiatrique, Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Service d'Hématologie Pédiatrique, Paris, France.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Dalle
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.affiliation: Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Service d'Hématologie Pédiatrique, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Service de Biologie Cellulaire, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: INSERM UMR 1131, Institut Universitaire d'Hématologie, Paris, France.|Université Paris Diderot, Paris Sorbonne Cité, Paris, France.|Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
mesh_terms: D000107:Acetylation; D000208:Acute Disease; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008745:Methylation; D018613:Microscopy, Confocal; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D059467:Transcriptome; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006657:Histones; D021122:Protein Subunits; D063151:Polycomb Repressive Complex 2; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins