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

Charlotte M. Niemeyer, Michelle W. Kang, Danielle H. Shin, Ingrid Furlan, Miriam Erlacher, Nancy J. Bunin, Severa Bunda, Jerry Z. Finklestein, Kathleen M. Sakamoto, Thomas A. Gorr, Parinda Mehta, Irene Schmid, Gabriele Kropshofer, Selim Corbacioglu, Peter J. Lang, Christoph Klein, Paul Gerhard Schlegel, Andrea Heinzmann, Michaela Schneider, Jan StarýMarry M Den van Heuvel-Eibrink, Henrik Hasle, Franco Locatelli, Debbie Sakai, Sophie Archambeault, Leslie Chen, Ryan C. Russell, Stephanie S. Sybingco, Michael Ohh, Benjamin S. Braun, Christian Flotho, Mignon L. Loh

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)641
Number of pages1
JournalNature Genetics
Issue number9
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics


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