title: Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.
abstract: CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Kang
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Danielle H
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Furlan
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Bunin
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Severa
authors.initials: S
authors.lastname: Bunda
authors.affiliation: Miller Children's Hospital/Harbor-UCLA, Jonathan Jaques Cancer Center, Long Beach, CA, United States.
authors.forename: Jerry Z
authors.initials: JZ
authors.lastname: Finklestein
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gorr
authors.affiliation: Division of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
authors.forename: Parinda
authors.initials: P
authors.lastname: Mehta
authors.affiliation: von Hauner Children's Hospital, LMU Munich University, Munich, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Schmid
authors.affiliation: University, Innsbruck, Austria; Department of Pediatrics and Adolescent Medicine, Medical.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Kropshofer
authors.affiliation: Department of Pediatrics, University of Ulm, Ulm, Germany.
authors.forename: Selim
authors.initials: S
authors.lastname: Corbacioglu
authors.affiliation: Dept. of Pediatrics, University of Tubingen, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lang
authors.affiliation: Department of Pediatrics, Medical School, Hannover.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Pediatrics, University of Wuerzburg, Germany.
authors.forename: Paul-Gerhard
authors.initials: PG
authors.lastname: Schlegel
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinzmann
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Pediatric Hematology and Oncology, Charles University Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Starý
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.affiliation: Pediatric Hematology/Oncology, University of Pavia Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Debbie
authors.initials: D
authors.lastname: Sakai
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Archambeault
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Sybingco
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Braun
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.affiliation: Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
mesh_terms: D002675:Child, Preschool; D003456:Cryptorchidism / Q000150:complications / Q000235:genetics; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile / Q000150:complications / Q000235:genetics*; D008297:Male; D010375:Pedigree; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000502:physiology
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human