Linked Life Data

20670954

Source:http://linkedlifedata.com/resource/pubmed/id/20670954

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2010-7-30
pubmed:abstractText
Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in all transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8- and CD3+CD4-CD8- ITK-SYK-positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-gamma. ITK-SYK-positive T-cells showed enhanced apoptosis resistance and INF-gamma production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
70
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6193-204
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:20670954-Animals, pubmed-meshheading:20670954-B-Lymphocytes, pubmed-meshheading:20670954-Bone Marrow Transplantation, pubmed-meshheading:20670954-Disease Models, Animal, pubmed-meshheading:20670954-Female, pubmed-meshheading:20670954-Humans, pubmed-meshheading:20670954-Immunophenotyping, pubmed-meshheading:20670954-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:20670954-Lymphocyte Activation, pubmed-meshheading:20670954-Lymphoma, T-Cell, pubmed-meshheading:20670954-Lymphoproliferative Disorders, pubmed-meshheading:20670954-Male, pubmed-meshheading:20670954-Mice, pubmed-meshheading:20670954-Mice, Inbred BALB C, pubmed-meshheading:20670954-Oncogene Proteins, Fusion, pubmed-meshheading:20670954-Point Mutation, pubmed-meshheading:20670954-Protein-Tyrosine Kinases, pubmed-meshheading:20670954-Proto-Oncogene Proteins c-cbl, pubmed-meshheading:20670954-T-Lymphocytes
pubmed:year
2010
pubmed:articleTitle
The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease.
pubmed:affiliation
Hematology/Oncology, University of Freiburg, Freiburg, Germany. christine.dierks@uniklinik-freiburg.de
pubmed:publicationType
Journal Article