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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We gratefully acknowledge the generous participation of the families included in this report. Supported in part by the US National Institutes of Health (CA113557 to M.L.L.); the V Foundation for Cancer Research (M.L.L. and B.S.B.); NIH/NCI (K08 CA103868 to B.S.B., R01 CA104282 to M.L.L. and B.S.B.); The Leukemia Lymphoma Society (6059-09, 2157-08 to M.L.L.); the Frank A. Campini Foundation (M.L.L. and B.S.B.); The Concern Foundation (B.S.B.); Deutsche Forschungsgemeinschaft (KR3473/1-1 to C.F.); Deutsche Krebshilfe (108220 to C.M.N. and C.F.); Deutsche José Carreras Leukämie-Stiftung (R08/19 to C.F.); the Canadian Cancer Society (16056 to M.O.); and the National Institute of General Medical Sciences (T32GM007618 to D.H.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.
The authors declare no competing financial interests.
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Niemeyer, C., Kang, M., Shin, D. et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42, 794–800 (2010). https://doi.org/10.1038/ng.641
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