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

被引：134

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

共 60 条

[1] Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia
Abdel-Wahab, Omar
Levine, Ross L.
[J]. BLOOD, 2013, 121 (18) : 3563 - 3572
[2] ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression
Abdel-Wahab, Omar
Adli, Mazhar
LaFave, Lindsay M.
Gao, Jie
Hricik, Todd
Shih, Alan H.
Pandey, Suveg
Patel, Jay P.
Chung, Young Rock
Koche, Richard
Perna, Fabiana
Zhao, Xinyang
Taylor, Jordan E.
Park, Christopher Y.
Carroll, Martin
Melnick, Ari
Nimer, Stephen D.
Jaffe, Jacob D.
Aifantis, Iannis
Bernstein, Bradley E.
Levine, Ross L.
[J]. CANCER CELL, 2012, 22 (02) : 180 - 193
[3] Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras
Ahmadian, MR
Stege, P
Scheffzek, K
Wittinghofer, A
[J]. NATURE STRUCTURAL BIOLOGY, 1997, 4 (09) : 686 - 689
[4] Phosphodiesterase-8A binds to and regulates Raf-1 kinase
Brown, Kim M.
Day, Jon P.
Huston, Elaine
Zimmermann, Bastian
Hampel, Kornelia
Christian, Frank
Romano, David
Terhzaz, Selim
Lee, Louisa C. Y.
Willis, Miranda J.
Morton, David B.
Beavo, Joseph A.
Shimizu-Albergine, Masami
Davies, Shireen A.
Kolch, Walter
Houslay, Miles D.
Baillie, George S.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (16) : E1533 - E1542
[5] Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium
Chan, Rebecca J.
Cooper, Todd
Kratz, Christian P.
Weiss, Brian
Loh, Mignon L.
[J]. LEUKEMIA RESEARCH, 2009, 33 (03) : 355 - 362
[6] Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia
Chang, Tiffany Y.
Dvorak, Christopher C.
Loh, Mignon L.
[J]. BLOOD, 2014, 124 (16) : 2487 - 2497
[7] Molecular architecture of human polycomb repressive complex 2
Ciferri, Claudio
Lander, Gabriel C.
Maiolica, Alessio
Herzog, Franz
Aebersold, Ruedi
Nogales, Eva
[J]. ELIFE, 2012, 1
[8] Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice
Cutts, Briony A.
Sjogren, Anna-Karin M.
Andersson, Karin M. E.
Wahlstrom, Annika M.
Karlsson, Christin
Swolin, Birgitta
Bergo, Martin O.
[J]. BLOOD, 2009, 114 (17) : 3629 - 3632
[9] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies
De Raedt, Thomas
Beert, Eline
Pasmant, Eric
Luscan, Armelle
Brems, Hilde
Ortonne, Nicolas
Helin, Kristian
Hornick, Jason L.
Mautner, Victor
Kehrer-Sawatzki, Hildegard
Clapp, Wade
Bradner, James
Vidaud, Michel
Upadhyaya, Meena
Legius, Eric
Cichowski, Karen
[J]. NATURE, 2014, 514 (7521) : 247 - +
[10] Eberth Alexander, 2009, Curr Protoc Cell Biol, VChapter 14, DOI 10.1002/0471143030.cb1409s43

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