Journal
NATURE GENETICS
Volume 42, Issue 9, Pages 794-U93Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.641
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Funding
- US National Institutes of Health [CA113557]
- V Foundation for Cancer Research
- NIH/NCI [K08 CA103868, R01 CA104282]
- Leukemia Lymphoma Society [6059-09, 2157-08]
- Frank A. Campini Foundation
- Concern Foundation
- Deutsche Forschungsgemeinschaft [KR3473/1-1]
- Deutsche Krebshilfe [108220]
- Deutsche Jose Carreras Leukamie-Stiftung [R08/19]
- Canadian Cancer Society [16056]
- National Institute of General Medical Sciences [T32GM007618]
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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.
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