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

Oliver Hantschel, Wolfgang Warsch, Eva Eckelhart, Ines Kaupe, Florian Grebien, Kay Uwe Wagner, Giulio Superti-Furga, Veronika Sexl

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)285-293
Number of pages9
JournalNature Chemical Biology
Volume8
Issue number3
DOIs
StatePublished - Mar 2012

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Leukemia
Maintenance
Myeloid Leukemia
Oncogene Proteins
Phosphotransferases
Apoptosis
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Hantschel, O., Warsch, W., Eckelhart, E., Kaupe, I., Grebien, F., Wagner, K. U., ... Sexl, V. (2012). BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nature Chemical Biology, 8(3), 285-293. https://doi.org/10.1038/nchembio.775

BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. / Hantschel, Oliver; Warsch, Wolfgang; Eckelhart, Eva; Kaupe, Ines; Grebien, Florian; Wagner, Kay Uwe; Superti-Furga, Giulio; Sexl, Veronika.

In: Nature Chemical Biology, Vol. 8, No. 3, 03.2012, p. 285-293.

Research output: Contribution to journalArticle

Hantschel, O, Warsch, W, Eckelhart, E, Kaupe, I, Grebien, F, Wagner, KU, Superti-Furga, G & Sexl, V 2012, 'BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia', Nature Chemical Biology, vol. 8, no. 3, pp. 285-293. https://doi.org/10.1038/nchembio.775
Hantschel O, Warsch W, Eckelhart E, Kaupe I, Grebien F, Wagner KU et al. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nature Chemical Biology. 2012 Mar;8(3):285-293. https://doi.org/10.1038/nchembio.775
Hantschel, Oliver ; Warsch, Wolfgang ; Eckelhart, Eva ; Kaupe, Ines ; Grebien, Florian ; Wagner, Kay Uwe ; Superti-Furga, Giulio ; Sexl, Veronika. / BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 3. pp. 285-293.
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