The genomic landscape of juvenile myelomonocytic leukemia

被引：221

作者：

Stieglitz, Elliot ^{[1
]}

Taylor-Weiner, Amaro N. ^{[2
]}

Chang, Tiffany Y. ^{[1
]}

Gelston, Laura C. ^{[1
]}

Wang, Yong-Dong ^{[3
]}

Mazor, Tali ^{[4
]}

Esquivel, Emilio ^{[1
]}

Yu, Ariel ^{[1
]}

Seepo, Sara ^{[2
]}

Olsen, Scott R. ^{[5
]}

Rosenberg, Mara ^{[2
]}

Archambeault, Sophie L. ^{[1
]}

Abusin, Ghada ^{[6
]}

Beckman, Kyle ^{[1
]}

Brown, Patrick A. ^{[7
]}

Briones, Michael ^{[8
]}

Carcamo, Benjamin ^{[9
]}

Cooper, Todd ^{[10
]}

Dahl, Gary V. ^{[11
]}

Emanuel, Peter D. ^{[12
]}

Fluchel, Mark N. ^{[13
]}

Goyal, Rakesh K. ^{[14
]}

Hayashi, Robert J. ^{[15
]}

Hitzler, Johann ^{[16
]}

Hugge, Christopher ^{[17
]}

Liu, Y. Lucy

Messinger, Yoav H. ^{[18
]}

Mahoney, Donald H., Jr. ^{[19
]}

Monteleone, Philip ^{[20
]}

Nemecek, Eneida R. ^{[21
]}

Roehrs, Philip A. ^{[22
]}

Schore, Reuven J. ^{[23
]}

Stine, Kimo C. ^{[24
]}

Takemoto, Clifford M. ^{[7
]}

Toretsky, Jeffrey A. ^{[25
,26
]}

Costello, Joseph F.

Olshen, Adam B. ^{[27
,28
]}

Stewart, Chip ^{[2
]}

Li, Yongjin ^{[3
]}

Ma, Jing ^{[29
]}

Gerbing, Robert B. ^{[30
]}

Alonzo, Todd A. ^{[31
]}

Getz, Gad ^{[2
,32
,33
,34
]}

Gruber, Tanja A. ^{[29
,35
]}

Golub, Todd R. ^{[2
,32
,36
,37
]}

Stegmaier, Kimberly ^{[2
,32
,36
,37
]}

Loh, Mignon L. ^{[1
,38
]}

机构：

[1] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA 94143 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA USA

[3] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[4] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[5] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA

[6] Univ Iowa, Carver Coll Med, Stead Family Dept Pediat, Iowa City, IA USA

[7] Johns Hopkins Univ Hosp, Dept Pediat, Baltimore, MD 21287 USA

[8] Emory Univ, Sch Med, Dept Pediat, Aflac Canc & Blood Disorder Ctr, Atlanta, GA USA

[9] Texas Tech Univ, Dept Pediat, El Paso, TX USA

[10] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA

[11] Stanford Sch Med, Dept Pediat, Stanford, CA USA

[12] Univ Arkansas Med Sci, Winthrop P Rockefeller Canc Inst, Little Rock, AR 72205 USA

[13] Univ Utah, Dept Pediat Hematol Oncol, Salt Lake City, UT USA

[14] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Dept Pediat, Pittsburgh, PA 15213 USA

[15] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[16] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada

[17] SSM Cardinal Glennon Childrens Med Ctr, Pediat Hematol Oncol, St Louis, MO USA

[18] Childrens Hosp & Clin Minnesota, Div Pediat Hematol Oncol, Minneapolis, MN USA

[19] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[20] Pediat Specialists Lehigh Valley Hosp, Pediat Hematol Oncol, Bethlehem, PA USA

[21] Oregon Hlth & Sci Univ, Pediat Bone Marrow Transplant Program, Portland, OR 97201 USA

[22] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA

[23] Childrens Natl Med Ctr, Div Pediat Oncol, Washington, DC 20010 USA

[24] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA

[25] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA

[26] Georgetown Univ, Dept Oncol, Washington, DC USA

[27] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[28] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[29] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[30] Childrens Oncol Grp, Dept Stat, Monrovia, CA USA

[31] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA

[32] Harvard Univ, Sch Med, Boston, MA USA

[33] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[34] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[35] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

[36] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[37] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA

[38] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 11期

基金：

美国国家卫生研究院;

关键词：

GATA2; MUTATIONS; NEUROFIBROMATOSIS TYPE-1; MONOMAC SYNDROME; POINT MUTATIONS; POOR-PROGNOSIS; CBL MUTATIONS; NF1; GENE; LNK; EXPRESSION; CHILDREN;

D O I：

10.1038/ng.3400

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

引用

页码：1326 / +

页数：10

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