PMID- 19901108
OWN - NLM
STAT- MEDLINE
DCOM- 20100121
LR  - 20211020
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 27
IP  - 36
DP  - 2009 Dec 20
TI  - Mutations of e3 ubiquitin ligase cbl family members constitute a novel common 
      pathogenic lesion in myeloid malignancies.
PG  - 6109-16
LID - 10.1200/JCO.2009.23.7503 [doi]
AB  - 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 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. 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.
FAU - Makishima, Hideki
AU  - Makishima H
AD  - Taussig Cancer Institute/R40, 9500 Euclid Ave, Cleveland OH 44195, USA.
FAU - Cazzolli, Heather
AU  - Cazzolli H
FAU - Szpurka, Hadrian
AU  - Szpurka H
FAU - Dunbar, Andrew
AU  - Dunbar A
FAU - Tiu, Ramon
AU  - Tiu R
FAU - Huh, Jungwon
AU  - Huh J
FAU - Muramatsu, Hideki
AU  - Muramatsu H
FAU - O'Keefe, Christine
AU  - O'Keefe C
FAU - Hsi, Eric
AU  - Hsi E
FAU - Paquette, Ronald L
AU  - Paquette RL
FAU - Kojima, Seiji
AU  - Kojima S
FAU - List, Alan F
AU  - List AF
FAU - Sekeres, Mikkael A
AU  - Sekeres MA
FAU - McDevitt, Michael A
AU  - McDevitt MA
FAU - Maciejewski, Jaroslaw P
AU  - Maciejewski JP
LA  - eng
GR  - K24 HL077522/HL/NHLBI NIH HHS/United States
GR  - R01 HL082983/HL/NHLBI NIH HHS/United States
GR  - U54 RR019391/RR/NCRR NIH HHS/United States
GR  - K24 HL-077522/HL/NHLBI NIH HHS/United States
GR  - R01HL-082983/HL/NHLBI NIH HHS/United States
GR  - S10 RR019391/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091109
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
SB  - IM
MH  - Chromosomes, Human, Pair 11
MH  - Frameshift Mutation
MH  - Humans
MH  - Immunohistochemistry
MH  - Karyotyping
MH  - Multivariate Analysis
MH  - *Mutation
MH  - Myeloproliferative Disorders/*enzymology/*genetics/pathology
MH  - Polymorphism, Single Nucleotide
MH  - Proto-Oncogene Proteins c-cbl/*genetics/metabolism
MH  - Uniparental Disomy/genetics
PMC - PMC3040009
COIS- Authors' disclosures of potential conflicts of interest and author contributions 
      are found at the end of this article.
EDAT- 2009/11/11 06:00
MHDA- 2010/01/22 06:00
PMCR- 2010/12/20
CRDT- 2009/11/11 06:00
PHST- 2009/11/11 06:00 [entrez]
PHST- 2009/11/11 06:00 [pubmed]
PHST- 2010/01/22 06:00 [medline]
PHST- 2010/12/20 00:00 [pmc-release]
AID - JCO.2009.23.7503 [pii]
AID - 37503 [pii]
AID - 10.1200/JCO.2009.23.7503 [doi]
PST - ppublish
SO  - J Clin Oncol. 2009 Dec 20;27(36):6109-16. doi: 10.1200/JCO.2009.23.7503. Epub 
      2009 Nov 9.