Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia

Hideki Muramatsu, Hideki Makishima, Anna M. Jankowska, Heather Cazzolli, Christine O'Keefe, Nao Yoshida, Yinyan Xu, Nobuhiro Nishio, Asahito Hama, Hiroshi Yagasaki, Yoshiyuki Takahashi, Koji Kato, Atsushi Manabe, Seiji Kojima, Jaroslaw P. Maciejewski

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    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 phenotypesshowedearlier 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.

    Original languageEnglish
    Pages (from-to)1969-1975
    Number of pages7
    JournalBlood
    Volume115
    Issue number10
    DOIs
    Publication statusPublished - Mar 11 2010

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    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Muramatsu, H., Makishima, H., Jankowska, A. M., Cazzolli, H., O'Keefe, C., Yoshida, N., ... Maciejewski, J. P. (2010). Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood, 115(10), 1969-1975. https://doi.org/10.1182/blood-2009-06-226340