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Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

Caye, Aurélie, Strullu, Marion, Guidez, Fabien, Cassinat, Bruno, Gazal, Steven, Fenneteau, Odile, Lainey, Elodie, Nouri, Kazem, Nakhaei-Rad, Saeideh, Dvorsky, Radovan, Lachenaud, Julie, Pereira, Sabrina, Vivent, Jocelyne, Verger, Emmanuelle, Vidaud, Dominique, Galambrun, Claire, Picard, Capucine, Petit, Arnaud, Contet, Audrey, Poirée, Marilyne, Sirvent, Nicolas, Méchinaud, Françoise, Adjaoud, Dalila, Paillard, Catherine, Nelken, Brigitte, Reguerre, Yves, Bertrand, Yves, Häussinger, Dieter, Dalle, Jean-Hugues, Ahmadian, Mohammad Reza, Baruchel, André, Chomienne, Christine, Cavé, Hélène·2015·Nature Genetics
DOI 10.1038/ng.3420
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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.

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Metadata

Authors
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, J.-H., Ahmadian, M. R., Baruchel, A., Chomienne, C., & Cavé, H.
ORCID
Petit, Arnaud
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2015-10-12
Volume
47
Issue
11
Pages
1334-1340
ISSN
  • 1061-4036
  • 1546-1718
DOI
10.1038/ng.3420
Cited by
189
References
6
Language
en
Licence
www.springer.com/tdm (tdm)

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CoChat. (2026). Citation check: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. https://app.cochat.ai/papers/10.1038/ng.3420
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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., . . . Cavé, H. (2015). Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nature Genetics. https://doi.org/10.1038/ng.3420