Linked Life Data

16585210

Source:http://linkedlifedata.com/resource/pubmed/id/16585210

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2006-4-4
pubmed:abstractText
Previous studies have shown that activation of the signal transducer and activator of transcription 5 (STAT5) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases (PTK). Because PIM-1 is a STAT5 target gene, we analyzed the role of the family of PIM serine/threonine kinases (PIM-1 to PIM-3) in PTK-mediated transformation of hematopoietic cells. Ba/F3 cells transformed to growth factor independence by various oncogenic PTKs (TEL/JAK2, TEL/TRKC, TEL/ABL, BCR/ABL, FLT3-ITD, and H4/PDGFbetaR) show abundant expression of PIM-1 and PIM-2. Suppression of PIM-1 activity had a negligible effect on transformation. In contrast, expression of kinase-dead PIM-2 mutant (PIM-2KD) led to a rapid decline of survival in Ba/F3 cells transformed by FLT3-ITD but not by other oncogenic PTKs tested. Coexpression of PIM-1KD and PIM-2KD abrogated growth factor-independent growth of Ba/F3 transformed by several PTKs, including BCR/ABL. Targeted down-regulation of PIM-2 by RNA interference (RNAi) selectively abrogated survival of Ba/F3 cells transformed by various Fms-like tyrosine kinase 3 (FLT3)-activating mutants [internal tandem duplication (ITD) and kinase domain] and attenuated growth of human cell lines containing FLT3 mutations. Interestingly, cells transformed by FLT3 and BCR/ABL mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2, or PIM-1 and PIM-2 by RNAi. Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia. Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3828-35
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16585210-Animals, pubmed-meshheading:16585210-Cell Survival, pubmed-meshheading:16585210-Cell Transformation, Neoplastic, pubmed-meshheading:16585210-Fusion Proteins, bcr-abl, pubmed-meshheading:16585210-Gene Transfer Techniques, pubmed-meshheading:16585210-Hematopoietic Stem Cells, pubmed-meshheading:16585210-Leukemia, Experimental, pubmed-meshheading:16585210-Mice, pubmed-meshheading:16585210-Mutation, pubmed-meshheading:16585210-Protein Kinase Inhibitors, pubmed-meshheading:16585210-Protein-Serine-Threonine Kinases, pubmed-meshheading:16585210-Protein-Tyrosine Kinases, pubmed-meshheading:16585210-Proto-Oncogene Proteins, pubmed-meshheading:16585210-Proto-Oncogene Proteins c-pim-1, pubmed-meshheading:16585210-RNA, Messenger, pubmed-meshheading:16585210-RNA, Small Interfering, pubmed-meshheading:16585210-fms-Like Tyrosine Kinase 3
pubmed:year
2006
pubmed:articleTitle
Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL.
pubmed:affiliation
Department of Pathology, Geneva Medical School, Geneva, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't