Nuclear factor of activated T-cells, NFATC1, governs FLT3(ITD)-driven hematopoietic stem cell transformation and a poor prognosis in AML

Solovey, Maria; Wang, Ying; Michel, Christian; Metzeler, Klaus H.; Herold, Tobias; Goethert, Joachim R.; Ellenrieder, Volker; Hessmann, Elisabeth; Gattenloehner, Stefan; Neubauer, Andreas; Pavlinic, Dinko; Benes, Vladimir; Rupp, Oliver und Burchert, Andreas (2019): Nuclear factor of activated T-cells, NFATC1, governs FLT3(ITD)-driven hematopoietic stem cell transformation and a poor prognosis in AML. In: Journal of Hematology & Oncology, Bd. 12, 72

Abstract

BackgroundAcute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication (ITD)-mutated FMS-like Tyrosine Kinase-3 (FLT3) have a dismal outcome. FLT3(ITD) triggers the proliferation of the quiescent hematopoietic stem cell (HSC) pool but fails to directly transform HSCs. While the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFAT2, NFATC1) is overexpressed in AML, it is unknown whether it plays a role in FLT3(ITD)-induced HSC transformation.MethodsWe generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3(ITD) positive HSC. Emerging genotypes were phenotypically, biochemically, and also transcriptionally characterized using RNA sequencing. We also retrospectively analyzed the overall survival of AML patients with different NFATC1 expression status.ResultsWe find that NFATC1 governs FLT3(ITD)-driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3(ITD)/NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3(ITD)-kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3(ITD)-dependent signaling output in HSC, involving augmented K-RAS signaling and a selective de novo recruitment of key HSC-transforming signaling pathways such as the Hedgehog- and WNT/B-Catenin signaling pathways. In human AML, NFATC1 overexpression is associated with poor overall survival.ConclusionsNFATC1 expression causes FLT3(ITD)-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1756-8722
• Sprache: Englisch