Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.
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.
Loh
Mignon L
ML
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, California, USA. lohm@peds.ucsf.edu
Sakai
Debbie S
DS
Flotho
Christian
C
Kang
Michelle
M
Fliegauf
Manfred
M
Archambeault
Sophie
S
Mullighan
Charles G
CG
Chen
Leslie
L
Bergstraesser
Eva
E
Bueso-Ramos
Carlos E
CE
Emanuel
Peter D
PD
Hasle
Henrik
H
Issa
Jean-Pierre
JP
van den Heuvel-Eibrink
Marry M
MM
Locatelli
Franco
F
Stary
Jan
J
Trebo
Monica
M
Wlodarski
Marcin
M
Zecca
Marco
M
Shannon
Kevin M
KM
Niemeyer
Charlotte M
CM
D002648:Child; D002675:Child, Preschool; D003062:Codon; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006720:Homozygote; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D015398:Signal Transduction
D003062:Codon; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human