title: The genomic landscape of juvenile myelomonocytic leukemia.
abstract: 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.
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Stieglitz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Amaro N
authors.initials: AN
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Tiffany Y
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Gelston
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Tali
authors.initials: T
authors.lastname: Mazor
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Emilio
authors.initials: E
authors.lastname: Esquivel
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Yu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Sara
authors.initials: S
authors.lastname: Seepo
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Scott
authors.initials: S
authors.lastname: Olsen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Archambeault
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abusin
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Beckman
authors.affiliation: Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, MA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Aflac Cancer and Blood Disorder Center, Atlanta, GA.
authors.forename: Michael
authors.initials: M
authors.lastname: Briones
authors.affiliation: Department of Pediatrics, Texas Tech University, El Paso, TX.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Carcamo
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, Seattle, WA.
authors.forename: Todd
authors.initials: T
authors.lastname: Cooper
authors.affiliation: Department of Pediatrics, Stanford School of Medicine, Stanford, CA.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Dahl
authors.affiliation: Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Emanuel
authors.affiliation: Department of Pediatric Hematology Oncology, University of Utah, Salt Lake City, UT.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Fluchel
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hayashi
authors.affiliation: Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Johann
authors.initials: J
authors.lastname: Hitzler
authors.affiliation: Pediatric Hematology Oncology, SSM Cardinal Glennon Children's Medical Center, Saint Louis, MO.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hugge
authors.affiliation: Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Y Lucy
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Division of Pediatric Hematology Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.
authors.forename: Yoav H
authors.initials: YH
authors.lastname: Messinger
authors.affiliation: Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Mahoney
authors.affiliation: Pediatric Hematology Oncology, Pediatric Specialists of Lehigh Valley Hospital, Bethlehem, PA.
authors.forename: Philip
authors.initials: P
authors.lastname: Monteleone
authors.affiliation: Pediatric Bone Marrow Transplant Program, Oregon Health & Science University, Portland, OR.
authors.forename: Eneida R
authors.initials: ER
authors.lastname: Nemecek
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, NC.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Roehrs
authors.affiliation: Division of Pediatric Oncology, Children's National Medical Center, Washington, DC.
authors.forename: Reuven J
authors.initials: RJ
authors.lastname: Schore
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Kimo C
authors.initials: KC
authors.lastname: Stine
authors.affiliation: Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, MA.
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Takemoto
authors.affiliation: Department of Pediatrics, Georgetown University, Washington, DC.|Department of Oncology, Georgetown University, Washington, DC.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Statistics, Children's Oncology Group, Monrovia, CA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.|Harvard Medical School, Boston, MA.|Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.|Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gruber
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Todd
authors.initials: T
authors.lastname: Golub
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.|Department of Pediatrics, Benioff Children's Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
mesh_terms: D000208:Acute Disease; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics*