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Nuclear factor of activated T-cells, NFATC1, governs FLT3ITD-driven hematopoietic stem cell transformation and a poor prognosis in AML.


ABSTRACT:

Background

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. 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.

Methods

We 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.

Results

We 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.

Conclusions

NFATC1 expression causes FLT3ITD-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.

SUBMITTER: Solovey M 

PROVIDER: S-EPMC6615262 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Nuclear factor of activated T-cells, NFATC1, governs FLT3<sup>ITD</sup>-driven hematopoietic stem cell transformation and a poor prognosis in AML.

Solovey Maria M   Wang Ying Y   Michel Christian C   Metzeler Klaus H KH   Herold Tobias T   Göthert Joachim R JR   Ellenrieder Volker V   Hessmann Elisabeth E   Gattenlöhner Stefan S   Neubauer Andreas A   Pavlinic Dinko D   Benes Vladimir V   Rupp Oliver O   Burchert Andreas A  

Journal of hematology & oncology 20190708 1


<h4>Background</h4>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. FLT3<sup>ITD</sup> 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<sup>IT  ...[more]

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