title: The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia.
abstract: PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis.
authors.affiliation: CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Schinnerl
authors.affiliation: CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria;
authors.forename: Klaus
authors.initials: K
authors.lastname: Fortschegger
authors.affiliation: CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kauer
authors.affiliation: Department of Pediatric Oncology and Hematology, Erasmus MC/Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; and.
authors.forename: João R M
authors.initials: JR
authors.lastname: Marchante
authors.affiliation: Division of Molecular Pathophysiology, Tyrolean Cancer Research Institute and Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.affiliation: Department of Pediatric Oncology and Hematology, Erasmus MC/Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; and.
authors.forename: Monique L
authors.initials: ML
authors.lastname: Den Boer
authors.affiliation: CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria;
authors.forename: Sabine
authors.initials: S
authors.lastname: Strehl
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics*; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; C507924:JAK2 protein, human; D053614:Janus Kinase 2