Leukemia, 2015-07, Vol.29 (7), p.1470-1477
2015
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- NFATc1 as a therapeutic target in FLT3-ITD-positive AML
- Ist Teil von
- Leukemia, 2015-07, Vol.29 (7), p.1470-1477
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0887-6924eISSN: 1476-5551DOI: 10.1038/leu.2015.95Titel-ID: cdi_proquest_miscellaneous_1722176577
- Format
- –
- Schlagworte
- Acute myelocytic leukemia, Acute myeloid leukemia, Apoptosis, Apoptosis - drug effects, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Blotting, Western, Care and treatment, Cell Proliferation - drug effects, Cell receptors, Chemotherapy, Cyclosporine - pharmacology, Cyclosporins, Drug resistance, Drug Resistance, Neoplasm - genetics, Flow Cytometry, fms-Like Tyrosine Kinase 3 - genetics, fms-Like Tyrosine Kinase 3 - metabolism, Gene Expression Profiling, Gene mutations, Genetic aspects, Health aspects, Humans, Immunoenzyme Techniques, Immunosuppressive Agents - pharmacology, Kinases, Leukemia, Leukemia research, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - metabolism, Leukemia, Myeloid, Acute - mortality, Leukemia, Myeloid, Acute - pathology, Lymphocytes, Methods, Molecular targeted therapy, Mutants, Mutation - genetics, Myeloid leukemia, Neoplasm Recurrence, Local - drug therapy, Neoplasm Recurrence, Local - metabolism, Neoplasm Recurrence, Local - mortality, Neoplasm Recurrence, Local - pathology, Neoplasm Staging, NF-AT protein, NFATC Transcription Factors - antagonists & inhibitors, NFATC Transcription Factors - genetics, NFATC Transcription Factors - metabolism, Niacinamide - analogs & derivatives, Niacinamide - pharmacology, Oligonucleotide Array Sequence Analysis, Patient outcomes, Phenylurea Compounds - pharmacology, Prognosis, Properties, Protein Kinase Inhibitors - pharmacology, Protein-tyrosine kinase, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleic acid, RNA, RNA, Messenger - genetics, RNA, Small Interfering - genetics, Survival Rate, Tandem Repeat Sequences - genetics, Therapeutic applications, Transcription factors, Tumor Cells, Cultured, Tyrosine