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

被引：141

作者：

Caye, Aurelie ^{[1
,2
,3
]}

Strullu, Marion ^{[1
,3
]}

Guidez, Fabien ^{[1
]}

Cassinat, Bruno ^{[4
]}

Gazal, Steven ^{[5
,6
]}

Fenneteau, Odile ^{[7
]}

Lainey, Elodie ^{[1
,2
,7
]}

Nouri, Kazem ^{[8
]}

Nakhaei-Rad, Saeideh ^{[8
]}

Dvorsky, Radovan ^{[8
]}

Lachenaud, Julie ^{[1
,3
]}

Pereira, Sabrina ^{[3
]}

Vivent, Jocelyne ^{[1
,3
]}

Verger, Emmanuelle ^{[1
,4
]}

Vidaud, Dominique ^{[9
,10
]}

Galambrun, Claire ^{[11
]}

Picard, Capucine ^{[12
,13
,14
]}

Petit, Arnaud ^{[15
]}

Contet, Audrey ^{[16
]}

Poiree, Marilyne ^{[17
]}

Sirvent, Nicolas ^{[18
]}

Mechinaud, Francoise ^{[19
]}

Adjaoud, Dalila ^{[20
]}

Paillard, Catherine ^{[21
]}

Nelken, Brigitte ^{[22
]}

Reguerre, Yves ^{[23
]}

Bertrand, Yves ^{[24
]}

Haeussinger, Dieter ^{[25
]}

Dalle, Jean-Hugues ^{[2
,26
]}

Ahmadian, Mohammad Reza ^{[8
]}

Baruchel, Andre ^{[2
,26
]}

Chomienne, Christine ^{[1
,2
,4
]}

Cave, Helene ^{[1
,2
,3
]}

机构：

[1] Inst Univ Hematol, INSERM, UMR 1131, Paris, France

[2] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France

[3] Hop Robert Debre, AP HP, Dept Genet, F-75019 Paris, France

[4] Hop St Louis, AP HP, Serv Biol Cellulaire, Paris, France

[5] Plateforme Genet Constitut Nord PfGC Nord, AP HP, Paris, France

[6] INSERM, UMR 1137, Infect Antimicrobial Modelling & Evolut IAME Lab, Paris, France

[7] Hop Robert Debre, AP HP, Serv Hematol Biol, F-75019 Paris, France

[8] Univ Dusseldorf, Fac Med, Inst Biochem & Mol Biol 2, Dusseldorf, Germany

[9] Univ Paris 05, Sorbonne Paris Cite, Equipe Accueil 7331, Fac Pharm Paris, Paris, France

[10] Hop Cochin, AP HP, Serv Biochim Genet, F-75674 Paris, France

[11] Hop La Timone, Assistance Publ Hop Marseille, Serv Hematol Pediat, Marseille, France

[12] Hop Necker Enfants Malad, AP HP, Ctr Etud Deficits Immunitaires, Immunohematol Unit, Paris, France

[13] Univ Paris 05, Sorbonne Paris Cite, Paris, France

[14] INSERM, UMR 1163, Inst Imagine, Lab Human Genet Infect Dis, Paris, France

[15] Hop Armand Trousseau, AP HP, Serv Hematol Oncol Pediat, Paris, France

[16] Hop Enfants Brabois, Serv Oncohematol Pediat, Vandoeuvre Les Nancy, France

[17] Hop Archet, Serv Oncohematol Pediat, Nice, France

[18] CHU Montpellier, Serv Oncohematol Pediat, Montpellier, France

[19] CHU Nantes, Serv Oncohematol Pediat, F-44035 Nantes 01, France

[20] CHU Grenoble, Serv Oncohematol Pediat, F-38043 Grenoble, France

[21] Hop Hautepierre, Serv Pediat, Strasbourg, France

[22] CHU Lille, Unite Hematol Pediat, F-59037 Lille, France

[23] Ctr Hosp Felix Guyon, St Denis, La Reunion, France

[24] Inst Hematooncol Pediat IHOP, Dept Immunol & Hematol Pediat, Lyon, France

[25] Univ Dusseldorf, Fac Med, Clin Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany

[26] Hop Robert Debre, AP HP, Serv Hematol Pediat, F-75019 Paris, France

来源：

NATURE GENETICS | 2015年 / 47卷 / 11期

关键词：

DETECTABLE CLONAL MOSAICISM; SOMATIC MUTATIONS; MULTIPLE MECHANISMS; COMPLEX; TRANSFORMATION; JARID2; CBL; HEMATOPOIESIS; ABNORMALITIES; HYPOTHESIS;

D O I：

10.1038/ng.3420

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1334 / +

页数：10

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