Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia

Nat Genet. 2010 Sep;42(9):794-800. doi: 10.1038/ng.641.

Charlotte M Niemeyer ^# ¹, Michelle W Kang ^# ², Danielle H Shin ^# ², Ingrid Furlan ¹, Miriam Erlacher ¹, Nancy J Bunin ³, Severa Bunda ⁴, Jerry Z Finklestein ⁵, Thomas A Gorr ¹, Parinda Mehta ⁶, Irene Schmid ⁷, Gabriele Kropshofer ⁸, Selim Corbacioglu ⁹, Peter J Lang ¹⁰, Christoph Klein ¹¹, Paul-Gerhard Schlegel ¹², Andrea Heinzmann ¹, Michaela Schneider ¹, Jan Starý ¹³, Marry M van den Heuvel-Eibrink ¹⁴, Henrik Hasle ¹⁵, Franco Locatelli ¹⁶, Debbie Sakai ², Sophie Archambeault ², Leslie Chen ², Ryan C Russell ⁴, Stephanie S Sybingco ⁴, Michael Ohh ⁴, Benjamin S Braun ², Christian Flotho ¹, Mignon L Loh ²

Affiliations

1 Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
2 Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
3 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
4 Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
5 Miller Children's Hospital/Harbor-UCLA, Jonathan Jaques Cancer Center, Long Beach, CA, United States.
6 Division of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
7 von Hauner Children's Hospital, LMU Munich University, Munich, Germany.
8 University, Innsbruck, Austria; Department of Pediatrics and Adolescent Medicine, Medical.
9 Department of Pediatrics, University of Ulm, Ulm, Germany.
10 Dept. of Pediatrics, University of Tubingen, Germany.
11 Department of Pediatrics, Medical School, Hannover.
12 Department of Pediatrics, University of Wuerzburg, Germany.
13 Department of Pediatric Hematology and Oncology, Charles University Prague, Prague, Czech Republic.
14 Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, Netherlands.
15 Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
16 Pediatric Hematology/Oncology, University of Pavia Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
# Contributed equally.

PMID: 20694012 DOI: 10.1038/ng.641

Abstract

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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