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. FLT3ITD 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 FLT3ITD-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 FLT3ITD 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 FLT3ITD-driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3ITD/NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3ITD-kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3ITD-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 FLT3ITD-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.
Highlights
Acute myeloid leukemia (AML) is mainly a fatal disease
Nuclear NFATC1 induces a rapidly lethal FLT3ITD-driven leukemia To address whether FLT3ITD synergizes with nuclear NFATC1 during FLT3ITD-driven AML transformation, we generated transgenic mice that constitutively express NFATC1 at the level of hematopoietic stem cells, along with Flt3ITD (Additional file 1: Figure S1)
CDNA under the control of a loxP–STOP–loxP cassette in the ROSA26 locus [7] were crossed with Cre-transgenic mice (Cre-ERT mice [24, 25]), in which tamoxifeninducible Cre-ERT recombinase is expressed under the control of the stem cell leukemia (Scl ) enhancer (SCLCre-ERT) and transgenic Flt3ITD mice [19], targeting NFATC1 expression to Flt3ITD-positive hematopoietic stem cells
Summary
Acute myeloid leukemia (AML) is mainly a fatal disease. AML evolution usually begins with sentinel de novo acquisition of mutations in epigenetic modifier genes such as DNMT3A, ASXL1, or TET2, which characterize clonal hematopoiesis of healthy individuals, referred to as CHIP or age-related clonal hematopoiesis, ARCH [1]. Progression from CHIP to AML is frequently associated by the consecutive acquisition of additional mutations such as in NPM1, RAS, KIT, or FLT3 [2]. The requirements, under which CHIP mutations become myeloid driver mutations, cooperate with other genetic or epigenetic changes to eventually cause AML, are not well understood. Acute 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. 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 FLT3ITD-induced HSC transformation
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