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NFATc1 as a therapeutic target in FLT3-ITD-positive AML

S K Metzelder1, C Michel1, M von Bonin2

  • 1Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany.

Leukemia
|May 16, 2015
PubMed

Insights

Nuclear factor NFATc1 drives sorafenib resistance in acute myeloid leukemia (AML) with internal tandem duplications (ITD) in the FLT3 receptor. Inhibiting NFATc1 with cyclosporine A (CsA) overcomes this resistance, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are linked to poor prognosis in acute myeloid leukemia (AML).
  • FLT3 inhibitors show limited long-term efficacy, necessitating research into resistance mechanisms and novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of nuclear factor of activated T cells, NFATc1, in mediating resistance to FLT3 inhibitors in AML.
  • To evaluate the potential of NFAT inhibition as a strategy to overcome sorafenib resistance in FLT3-ITD+ AML.

Main Methods:

  • Assessed NFATc1 expression in FLT3-ITD+ AML.
  • Utilized inducible short hairpin RNA for NFATc1 knockdown.
  • Employed pharmacological NFAT inhibition with cyclosporine A (CsA) and VIVIT.
  • Investigated the impact of NFATc1 modulation on sorafenib-induced apoptosis in FLT3-ITD+ cells and primary AML samples.
  • Analyzed clinical data of FLT3-ITD+ AML patients treated with CsA.

Main Results:

  • NFATc1 was frequently overexpressed in FLT3-ITD+ AML.
  • NFATc1 knockdown or inhibition with CsA/VIVIT enhanced sorafenib-induced apoptosis in FLT3-ITD+ cells.
  • CsA effectively overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML.
  • Constitutive nuclear NFATc1 expression conferred robust sorafenib resistance.
  • FLT3-ITD+ AML patients receiving CsA showed superior outcomes compared to FLT3-WT AML patients.

Conclusions:

  • NFATc1 is identified as a novel mediator of sorafenib resistance in FLT3-ITD+ AML.
  • Inhibition of NFATc1 by CsA counteracts sorafenib resistance and may improve treatment outcomes in AML.
  • Targeting NFATc1 presents a promising therapeutic strategy for overcoming FLT3 inhibitor resistance in AML.

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