Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.
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.
Niemeyer
Charlotte M
CM
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Kang
Michelle W
MW
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Shin
Danielle H
DH
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Furlan
Ingrid
I
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Erlacher
Miriam
M
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Bunin
Nancy J
NJ
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Bunda
Severa
S
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Finklestein
Jerry Z
JZ
Miller Children's Hospital/Harbor-UCLA, Jonathan Jaques Cancer Center, Long Beach, CA, United States.
Gorr
Thomas A
TA
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Mehta
Parinda
P
Division of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Schmid
Irene
I
von Hauner Children's Hospital, LMU Munich University, Munich, Germany.
Kropshofer
Gabriele
G
University, Innsbruck, Austria; Department of Pediatrics and Adolescent Medicine, Medical.
Corbacioglu
Selim
S
Department of Pediatrics, University of Ulm, Ulm, Germany.
Lang
Peter J
PJ
Dept. of Pediatrics, University of Tubingen, Germany.
Klein
Christoph
C
Department of Pediatrics, Medical School, Hannover.
Schlegel
Paul-Gerhard
PG
Department of Pediatrics, University of Wuerzburg, Germany.
Heinzmann
Andrea
A
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Schneider
Michaela
M
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Starý
Jan
J
Department of Pediatric Hematology and Oncology, Charles University Prague, Prague, Czech Republic.
van den Heuvel-Eibrink
Marry M
MM
Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, Netherlands.
Hasle
Henrik
H
Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
Locatelli
Franco
F
Pediatric Hematology/Oncology, University of Pavia Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Sakai
Debbie
D
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Archambeault
Sophie
S
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Chen
Leslie
L
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Russell
Ryan C
RC
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Sybingco
Stephanie S
SS
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Ohh
Michael
M
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Braun
Benjamin S
BS
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Flotho
Christian
C
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Loh
Mignon L
ML
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
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
D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human