Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.
Fiche publication
Date publication
novembre 2015
Journal
Nature genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, Lainey E, Nouri K, Nakhaei-Rad S, Dvorsky R, Lachenaud J, Pereira S, Vivent J, Verger E, Vidaud D, Galambrun C, Picard C, Petit A, Contet A, Poirée M, Sirvent N, Méchinaud F, Adjaoud D, Paillard C, Nelken B, Reguerre Y, Bertrand Y, Häussinger D, Dalle JH, Ahmadian MR, Baruchel A, Chomienne C, Cavé H
Lien Pubmed
Résumé
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.
Mots clés
Acetylation, Acute Disease, Child, Child, Preschool, DNA Copy Number Variations, Disease Progression, Female, Gene Regulatory Networks, genetics, Histones, metabolism, Humans, Infant, Leukemia, Myeloid, genetics, Leukemia, Myelomonocytic, Juvenile, genetics, Male, Methylation, Microscopy, Confocal, Mutation, Phosphatidylinositol 3-Kinases, genetics, Polycomb Repressive Complex 2, genetics, Protein Subunits, genetics, Sequence Analysis, DNA, methods, Signal Transduction, genetics, Survival Analysis, Transcriptome, ras Proteins, genetics
Référence
Nat Genet. 2015 11;47(11):1334-40