title: Janus kinase 2 regulates Bcr-Abl signaling in chronic myeloid leukemia.
abstract: Despite the success of imatinib mesylate (IM) in the early chronic phase of chronic myeloid leukemia (CML), patients are resistant to IM and other kinase inhibitors in the later stages of CML. Our findings indicate that inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells overcomes IM resistance although the precise mechanism of Jak2 action is unknown. Knocking down Jak2 in Bcr-Abl+ cells reduced levels of the Bcr-Abl protein and also the phosphorylation of Tyr177 of Bcr-Abl, and Jak2 overexpression rescued these knockdown effects. Treatment of Bcr-Abl+ cells with Jak2 inhibitors for 4-6 h but not with IM also reduced Bcr-Abl protein and pTyr177 levels. In vitro kinase experiments performed with recombinant Jak2 showed that Jak2 readily phosphorylated Tyr177 of Bcr-Abl (a Jak2 consensus site, YvnV) whereas c-Abl did not. Importantly, Jak2 inhibition decreased pTyr177 Bcr-Abl in immune complexes but did not reduce levels of Bcr-Abl, suggesting that the reduction of Bcr-Abl by Jak2 inhibition is a separate event from phosphorylation of Tyr177. Jak2 inhibition by chemical inhibitors (TG101209/WP1193) and Jak2 knockdown diminished the activation of Ras, PI-3 kinase pathways and reduced levels of pTyrSTAT5. These findings suggest that Bcr-Abl stability and oncogenic signaling in CML cells are under the control of Jak2.
authors.affiliation: Department of Molecular Pathology, M.D. Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: A
authors.initials: A
authors.lastname: Samanta
authors.forename: B
authors.initials: B
authors.lastname: Perazzona
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: H
authors.initials: H
authors.lastname: Modi
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.forename: W
authors.initials: W
authors.lastname: Priebe
authors.forename: R
authors.initials: R
authors.lastname: Arlinghaus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; D014443:Tyrosine; C490895:GAB2 protein, human; C522865:TG101209; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human