TY - JOUR
T1 - BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia
AU - Hantschel, Oliver
AU - Warsch, Wolfgang
AU - Eckelhart, Eva
AU - Kaupe, Ines
AU - Grebien, Florian
AU - Wagner, Kay Uwe
AU - Superti-Furga, Giulio
AU - Sexl, Veronika
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.775
DO - 10.1038/nchembio.775
M3 - Article
C2 - 22286129
AN - SCOPUS:84857143671
SN - 1552-4450
VL - 8
SP - 285
EP - 293
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 3
ER -