title: NFATc1 as a therapeutic target in FLT3-ITD-positive AML.
abstract: Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Metzelder
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Michel
authors.affiliation: Universitätsklinikum Carl-Gustav-Carus, Technische Universität Dresden, Fetscherstraße Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Bonin
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rehberger
authors.affiliation: Universitätsmedizin Göttingen, Klinik für Gastroenterologie II, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Hessmann
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Inselmann
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Solovey
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Sohlbach
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brendel
authors.affiliation: Division of Molecular Oncology, Philipps Universität, Marburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Division of Molecular Oncology, Philipps Universität, Marburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Charles
authors.affiliation: Institut für Pathologie, Universitätsklinikum Gießen und Marburg, Standort Gießen, Gießen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ten Haaf
authors.affiliation: Universitätsmedizin Göttingen, Klinik für Gastroenterologie II, Göttingen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Ellenrieder
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Neubauer
authors.affiliation: Institut für Pathologie, Universitätsklinikum Gießen und Marburg, Standort Gießen, Gießen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gattenlöhner
authors.affiliation: Universitätsklinikum Carl-Gustav-Carus, Technische Universität Dresden, Fetscherstraße Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Burchert
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D015996:Survival Rate; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D009536:Niacinamide; D016572:Cyclosporine; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3