title: Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.
abstract: The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohr
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Doebele
authors.affiliation: Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
authors.forename: Federico
authors.initials: F
authors.lastname: Comoglio
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Berg
authors.affiliation: Chronix Biomedical, Goetheallee 8, 37073 Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Beck
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37073 Göttingen, Germany.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Corso
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37073 Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Institute of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073 Göttingen, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Wachter
authors.affiliation: Institute of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073 Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schnütgen
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Anjali
authors.initials: A
authors.lastname: Cremer
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Haetscher
authors.affiliation: Department of Hematology and Oncology, University of Halle, Ernst-Grube-Street 40, 06120 Halle, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Arefeh
authors.initials: A
authors.lastname: Rouhi
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Su sahlgrenska, 41345 Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Palmqvist
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Goethe University, Sandhofstraße 1, 60590 Frankfurt, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bönig
authors.affiliation: Department of Hematology and Oncology, University of Halle, Ernst-Grube-Street 40, 06120 Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kuchenbauer
authors.affiliation: Chronix Biomedical, Goetheallee 8, 37073 Göttingen, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.affiliation: Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Bioanalytics, Georg August University, Robert-Koch-Straße 40, 37073 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: thomas.oellerich@kgu.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
mesh_terms: D000818:Animals; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D039661:Integrin beta3; C000616391:MEIS1 protein, human; C542542:MIRN146 microRNA, human; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: Hox genes; PU.1; Syk; leukemia; microRNA; signal transduction