title: Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies.
abstract: OBJECTIVE
  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 c-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Taussig Cancer Institute/R40, 9500 Euclid Ave, Cleveland OH 44195, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Heather
authors.initials: H
authors.lastname: Cazzolli
authors.forename: Hadrian
authors.initials: H
authors.lastname: Szpurka
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunbar
authors.forename: Ramon
authors.initials: R
authors.lastname: Tiu
authors.forename: Jungwon
authors.initials: J
authors.lastname: Huh
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Christine
authors.initials: C
authors.lastname: O'Keefe
authors.forename: Eric
authors.initials: E
authors.lastname: Hsi
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Paquette
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D002880:Chromosomes, Human, Pair 11; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D015999:Multivariate Analysis; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism; D024182:Uniparental Disomy / Q000235:genetics
chemical_list: D050721:Proto-Oncogene Proteins c-cbl