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.

Department of Laboratory Medicine and Pathobiology University of Toronto 1 King's College Circle Toronto Ontario M5S 1A8 Canada

Department of Pediatric Hematology and Oncology Charles University Prague Prague Czech Republic

Department of Pediatric Oncology Hematology Erasmus Medical Center Rotterdam Netherlands

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark

Department of Pediatrics and Adolescent Medicine University of Freiburg Freiburg Germany

Department of Pediatrics and the Comprehensive Cancer Center University of California San Francisco San Francisco CA United States

Department of Pediatrics Medical School Hannover

Department of Pediatrics University of Ulm Ulm Germany

Department of Pediatrics University of Wuerzburg Germany

Dept of Pediatrics University of Tubingen Germany

Division of Hematology Oncology Cincinnati Children's Hospital Medical Center Cincinnati OH United States

Division of Oncology Children's Hospital of Philadelphia Philadelphia PA United States

Miller Children's Hospital Harbor UCLA Jonathan Jaques Cancer Center Long Beach CA United States

Pediatric Hematology Oncology University of Pavia Fondazione IRCCS Policlinico San Matteo Pavia Italy

University Innsbruck Austria; Department of Pediatrics and Adolescent Medicine Medical

von Hauner Children's Hospital LMU Munich University Munich Germany

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RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia

RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia