title: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia.
abstract: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypes showed earlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH 44195, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: Heather
authors.initials: H
authors.lastname: Cazzolli
authors.forename: Christine
authors.initials: C
authors.lastname: O'Keefe
authors.forename: Nao
authors.initials: N
authors.lastname: Yoshida
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Xu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishio
authors.forename: Asahito
authors.initials: A
authors.lastname: Hama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagasaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human