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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-36009

Niemeyer, C M; Kang, M W; Shin, D H; Furlan, I; Erlacher, M; Bunin, N J; Bunda, S; Finklestein, J Z; Sakamoto, K M; Gorr, T A; Mehta, P; Schmid, I; Kropshofer, G; Corbacioglu, S; Lang, P J; Klein, C; Schlegel, P-G; Heinzmann, A; Schneider, M; Starý, J; van den Heuvel-Eibrink, M M; Hasle, H; Locatelli, F; Sakai, D; Archambeault, S; Chen, L; Russell, R C; Sybingco, S S; Ohh, M; Braun, B S; Flotho, C; Loh, M L (2010). Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics, 42(9):794-800.

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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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Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Deposited On:11 Nov 2010 12:30
Last Modified:02 Jan 2014 09:47
Publisher:Nature Publishing Group
Publisher DOI:10.1038/ng.641
PubMed ID:20694012

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