Journal
NATURE GENETICS
Volume 47, Issue 11, Pages 1334-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3420
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Funding
- Ligue contre le Cancer (LCC)-Ile-de-France
- Societe Francaise de Lutte contre les Cancers et Leucemies de l'Enfant (SFCE)
- Association pour la Recherche et pour les Etudes dans les Maladies Infantiles Graves (AREMIG, Nancy)
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [Collaborative Research Center 974 SFB 974]
- International Graduate School of Protein Science and Technology (iGRASP)
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Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations1-3. 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.
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