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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Proliferation / drug effects
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Cyclosporine / pharmacology
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Drug Resistance, Neoplasm / genetics*
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Flow Cytometry
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Gene Expression Profiling
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Humans
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Immunoenzyme Techniques
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Immunosuppressive Agents / pharmacology
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / mortality
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Leukemia, Myeloid, Acute / pathology
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Mutation / genetics
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NFATC Transcription Factors / antagonists & inhibitors
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism*
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / mortality
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Neoplasm Recurrence, Local / pathology
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Neoplasm Staging
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Niacinamide / analogs & derivatives*
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Niacinamide / pharmacology
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Oligonucleotide Array Sequence Analysis
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Phenylurea Compounds / pharmacology*
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Prognosis
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Sorafenib
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Survival Rate
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Tandem Repeat Sequences / genetics*
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Tumor Cells, Cultured
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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Biomarkers, Tumor
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Immunosuppressive Agents
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NFATC Transcription Factors
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NFATC1 protein, human
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Phenylurea Compounds
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Protein Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Niacinamide
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Cyclosporine
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Sorafenib
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3