title: RUNX1 cooperates with FLT3-ITD to induce leukemia.
abstract: Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identifiedHhexas a direct target of RUNX1 and FLT3-ITD stimulation and confirmed highHHEXexpression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Kira
authors.identifier: 0000-0003-0800-8472
authors.initials: K
authors.lastname: Behrens
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Maul
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.|Virus Genomics, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Nilgün
authors.initials: N
authors.lastname: Tekin
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Neele
authors.identifier: 0000-0002-3322-8314
authors.initials: N
authors.lastname: Kriebitzsch
authors.affiliation: Viral Transformation, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Indenbirken
authors.affiliation: Engelhardt Institute for Molecular Biology, 119991 Moscow, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Prassolov
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Ursula
authors.identifier: 0000-0002-7837-5422
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Medicine, Hematology/Oncology, Johann Wolfgang Goethe-University, 60590 Frankfurt am Main, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Department of Hematology, Institute for Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.affiliation: Retroviral Pathogenesis, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany c.stocking@uke.de.
authors.forename: Carol
authors.identifier: 0000-0003-4440-2442
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D051379:Mice; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3