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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2011

AutorInnen: Grebien, F; Hantschel, O; Wojcik, J; Kaupe, I; Kovacic, B; Wyrzucki, AM; Gish, GD; Cerny-Reiterer, S; Koide, A; Beug, H; Pawson, T; Valent, P; Koide, S; Superti-Furga, G

Titel: Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis.

Quelle: Cell. 2011; 147(2):306-319



Autor/innen der Vetmeduni Vienna:

Grebien Florian

Diese Publikation wurde nicht im Namen der Vetmeduni Vienna erstellt und ist deshalb ausschließlich der persönlichen Publikationsliste des/der Autors/Autorin zugeordnet!


Abstract:
Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention.

Keywords Pubmed: Amino Acid Sequence
Animals
Base Sequence
Benzamides
Cells, Cultured
Fusion Proteins, bcr-abl/antagonists & inhibitors*
Fusion Proteins, bcr-abl/chemistry*
Fusion Proteins, bcr-abl/metabolism
Humans
Imatinib Mesylate
Isoleucine/metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology*
Mice
Models, Molecular
Molecular Sequence Data
Piperazines/pharmacology
Protein Kinase Inhibitors/pharmacology
Protein-Tyrosine Kinases/antagonists & inhibitors*
Protein-Tyrosine Kinases/chemistry*
Protein-Tyrosine Kinases/metabolism
Pyrimidines/pharmacology
Signal Transduction
src Homology Domains


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