Title : ( Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network )
Authors: Aurelie Caye , Marion Strullu , Fabien Guidez , Bruno Cassinat , Steven Gazal , Odile Fenneteau , Elodie Lainey , Kazem Nouri , Saeideh Nakhaeirad , Radovan Dvorsky , Julie Lachenaud , Sabrina Pereira , Jocelyne Vivent , Emmanuelle Verger , Dominique Vidaud , Claire Galambrun , Capucine Picard , Arnaud Petit , Audrey Contet , Marilyne Poiree , Nicolas Sirvent , Francoise Mechinaud , Dalila Adjaoud , Catherine Paillard , Brigitte Nelken , Yves Reguerre , Yves Bertrand , Dieter Haussinger , Jean-Hugues Dalle , Mohammad Reza Ahmadian , Andre Baruchel , Christine Chomienne , Helene Cave ,
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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.
Keywords
, JMML, RAC, NRAS
@article{paperid:1077970,
author = {Aurelie Caye and Marion Strullu and Fabien Guidez and Bruno Cassinat and Steven Gazal and Odile Fenneteau and Elodie Lainey and Kazem Nouri and Nakhaeirad, Saeideh and Radovan Dvorsky and Julie Lachenaud and Sabrina Pereira and Jocelyne Vivent and Emmanuelle Verger and Dominique Vidaud and Claire Galambrun and Capucine Picard and Arnaud Petit and Audrey Contet and Marilyne Poiree and Nicolas Sirvent and Francoise Mechinaud and Dalila Adjaoud and Catherine Paillard and Brigitte Nelken and Yves Reguerre and Yves Bertrand and Dieter Haussinger and Jean-Hugues Dalle and Mohammad Reza Ahmadian and Andre Baruchel and Christine Chomienne and Helene Cave},
title = {Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network},
journal = {Nature Genetics},
year = {2015},
volume = {47},
number = {11},
month = {November},
issn = {1061-4036},
pages = {1334--1340},
numpages = {6},
keywords = {JMML; RAC; NRAS},
}
%0 Journal Article
%T Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network
%A Aurelie Caye
%A Marion Strullu
%A Fabien Guidez
%A Bruno Cassinat
%A Steven Gazal
%A Odile Fenneteau
%A Elodie Lainey
%A Kazem Nouri
%A Nakhaeirad, Saeideh
%A Radovan Dvorsky
%A Julie Lachenaud
%A Sabrina Pereira
%A Jocelyne Vivent
%A Emmanuelle Verger
%A Dominique Vidaud
%A Claire Galambrun
%A Capucine Picard
%A Arnaud Petit
%A Audrey Contet
%A Marilyne Poiree
%A Nicolas Sirvent
%A Francoise Mechinaud
%A Dalila Adjaoud
%A Catherine Paillard
%A Brigitte Nelken
%A Yves Reguerre
%A Yves Bertrand
%A Dieter Haussinger
%A Jean-Hugues Dalle
%A Mohammad Reza Ahmadian
%A Andre Baruchel
%A Christine Chomienne
%A Helene Cave
%J Nature Genetics
%@ 1061-4036
%D 2015
