title: BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia.
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.
authors.affiliation: CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Warsch
authors.forename: Eva
authors.initials: E
authors.lastname: Eckelhart
authors.forename: Ines
authors.initials: I
authors.lastname: Kaupe
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2