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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2012

AutorInnen: Hantschel, O; Warsch, W; Eckelhart, E; Kaupe, I; Grebien, F; Wagner, KU; Superti-Furga, G; Sexl, V

Titel: BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia.

Quelle: Nat Chem Biol. 2012; 8(3):285-293



Autor/innen der Vetmeduni Vienna:

Grebien Florian
Sexl Veronika
Warsch Wolfgang

Beteiligte Vetmed-Organisationseinheiten
Institut für Pharmakologie und Toxikologie


Abstract:
Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option for CML patients. Using murine leukemia models combined with inducible ablation of JAK2, we show JAK2 dependence for initial lymphoid transformation, which is lost once leukemia is established. In contrast, initial myeloid transformation and leukemia maintenance were independent of JAK2. Nevertheless, several JAK2 TKIs induced apoptosis in BCR-ABL(+) cells irrespective of the presence of JAK2. This is caused by the previously unknown direct "off-target" inhibition of BCR-ABL. Cellular and enzymatic analyses suggest that BCR-ABL phosphorylates STAT5 directly. Our findings suggest uncoupling of the canonical JAK2-STAT5 module upon BCR-ABL expression, thereby making JAK2 targeting dispensable. Thus, attempts to pharmacologically target STAT5 in BCR-ABL(+) diseases need to focus on STAT5 itself.

Keywords Pubmed: Animals
Antineoplastic Agents/pharmacology
Benzamides
Cell Line, Tumor
Fusion Proteins, bcr-abl/antagonists & inhibitors
Fusion Proteins, bcr-abl/metabolism*
HEK293 Cells
Humans
Janus Kinase 2/antagonists & inhibitors
Janus Kinase 2/deficiency
Janus Kinase 2/metabolism*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Piperazines/pharmacology
Pyrimidines/pharmacology
STAT5 Transcription Factor/antagonists & inhibitors
STAT5 Transcription Factor/metabolism*
Signal Transduction*/drug effects
U937 Cells


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