Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.

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Mignon L Loh
Debbie S Sakai
Christian Flotho
Michelle Kang
Manfred Fliegauf
Sophie Archambeault
Charles G Mullighan
Leslie Chen
Eva Bergstraesser
Carlos E Bueso-Ramos
Peter D Emanuel
Henrik Hasle
Jean-Pierre Issa
Marry M van den Heuvel-Eibrink
Franco Locatelli
Jan Stary
Monica Trebo
Marcin Wlodarski
Marco Zecca
Kevin M Shannon
Charlotte M Niemeyer
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Scientific Abstract: 
Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples. Thirteen of these mutations alter codon Y371. In this report, we also demonstrate that CBL and RAS/PTPN11 mutations were mutually exclusive in these patients. Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML.