title: Depletion of STAT5 blocks TEL-SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice.
abstract: The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK(wt), TEL-SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK(wt) enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK-SYK caused lethal T-cell lymphomas and the cytoplasmic TEL-SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL-SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL-SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL-SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.
authors.affiliation: 1] Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany [2] University of Freiburg, Schaenzlestrasse 1, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sprissler
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Belenki
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Maurer
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Aumann
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: T A
authors.initials: TA
authors.lastname: Müller
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kissel
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hülsdünker
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Alexandrovski
authors.affiliation: 1] Institut für Molekulare Medizin und Zellforschung, University of Freiburg, Stefan-Meier-Str. 17, Freiburg, Germany [2] Centre for Biological Signaling Studies BIOSS, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Brummer
authors.affiliation: 1] Department of Pathology, University Medical Center Freiburg, Freiburg, Germany [2] Institut für Molekulare Medizin und Zellforschung, University of Freiburg, Stefan-Meier-Str. 17, Freiburg, Germany [3] Centre for Biological Signaling Studies BIOSS, Freiburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Jumaa
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Duyster
authors.affiliation: 1] Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany [2] Centre for Biological Signaling Studies BIOSS, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Dierks
mesh_terms: D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000072377:Syk Kinase; D000097764:ETS Translocation Variant 6 Protein; C000606897:Syk protein, mouse