Mutations in CBL occur frequently in juvenile myelomonocytic leukemia

• Published in: Blood Vol. 114; no. 9; pp. 1859 - 1863
• Main Authors: Loh, Mignon L., Sakai, Debbie S., Flotho, Christian, Kang, Michelle, Fliegauf, Manfred, Archambeault, Sophie, Mullighan, Charles G., Chen, Leslie, Bergstraesser, Eva, Bueso-Ramos, Carlos E., Emanuel, Peter D., Hasle, Henrik, Issa, Jean-Pierre, van den Heuvel-Eibrink, Marry M., Locatelli, Franco, Starý, Jan, Trebo, Monica, Wlodarski, Marcin, Zecca, Marco, Shannon, Kevin M., Niemeyer, Charlotte M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 27.08.2009; Americain Society of Hematology; American Society of Hematology
• Series: Myeloid Neoplasia
• Subjects: Biological and medical sciences; Child; Child, Preschool; Codon; Female; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - cytology; Homozygote; Humans; Infant; Leukemia, Myelomonocytic, Juvenile - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Male; Medical sciences; Mutation; Myeloid Neoplasia; Proto-Oncogene Proteins c-cbl - genetics; Signal Transduction; Human; Myeloproliferative syndrome; Gene; Genetics; Juvenile myelomonocytic leukemia; Malignant hemopathy; Mutation; Child; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-01-198416

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.