10.17192/z2019.0457
Solovey, Maria
Maria
Solovey
Nuclear factor of activated T-cells, NFATC1, governs FLT3-ITD-driven hematopoietic stem cell transformation and a poor prognosis in AML
Nuclear factor of activated T-cells, NFATC1, fördert eine FLT3-ITD-assoziierte Transformation der hämatopoetischen Stammzellen, sowie eine ungünstige Prognose in der AML
Philipps-Universität Marburg
2019
Medical sciences Medicine
Medizin
FLT3-ITD
NFATC1
AML
Burchert, Andreas (Prof. Dr.)
Innere Medizin
2020-02-28
2019-12-12
en
DoctoralThesis
https://archiv.ub.uni-marburg.de/diss/z2019/0457
urn:nbn:de:hebis:04-z2019-04573
https://archiv.ub.uni-marburg.de/diss/z2019/0457/cover.png
application/pdf
https://creativecommons.org/licenses/by-nc-sa/4.0
Internal tandem duplication ITD-mutated FMS-like Tyrosine Kinase-3 (FLT3) is associated with poor prognosis in patients with acute myeloid leukemia (AML). In mouse models, it has been shown that although FLT3ITD increases proliferation of the hematopoietic stem cells (HSC), it doesn't lead to full transformation of the HSC and development of AML phenotype. We have previously shown that the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFATC1) is overexpressed in FLT3ITD-positive AML, yet its role in the transformation and AML development is unknown.
We generated a triple transgenic mouse model, in which tamoxifen-inducible HSC specific Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3ITD-positive HSC. The triple transgenic mice and the respective controls 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.
We find that NFATC1 governs FLT3ITD-driven stem cell, progenitor and monocyte expansion and transformation, causing a fully penetrant lethal AML. FLT3ITD/NFATC1-AML is transplantable in sub-lethally irradiated WT recipients and confers resistance to the FLT3ITD-kinase inhibitor quizartinib. The bulk RNA sequencing analysis showed that in the HSC, the interplay of NFATC1 and FLT3ITD changes the transcriptional landscape, involving augmented K-RAS signaling and a selective de novo recruitment of key proliferative and HSC-transforming signaling pathways such as the Hedgehog- and WNT-beta-catenin. In human AML, NFATC1 overexpression is associated with poor overall survival.