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Mutations of E3 Ubiquitin Ligase Cbl Family Members Constitute a Novel Common Pathogenic Lesion in Myeloid Malignancies

Title
Mutations of E3 Ubiquitin Ligase Cbl Family Members Constitute a Novel Common Pathogenic Lesion in Myeloid Malignancies
Authors
Makishima, HidekiCazzolli, HeatherSzpurka, HadrianDunbar, AndrewTiu, RamonHuh, JungwonMuramatsu, HidekiO'Keefe, ChristineHsi, EricPaquette, Ronald L.Kojima, SeijiList, Alan F.Sekeres, Mikkael A.McDevitt, Michael A.Maciejewski, Jaroslaw P.
Ewha Authors
허정원
SCOPUS Author ID
허정원scopus
Issue Date
2009
Journal Title
JOURNAL OF CLINICAL ONCOLOGY
ISSN
0732-183XJCR Link
Citation
vol. 27, no. 36, pp. 6109 - 6116
Publisher
AMER SOC CLINICAL ONCOLOGY
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
Purpose Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in o-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism.
DOI
10.1200/JCO.2009.23.7503
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의학전문대학원 > 의학과 > Journal papers
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