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

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...

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Bibliographic Details
Main Author: Solovey, Maria
Contributors: Burchert, Andreas (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2019
Subjects:
AML
Online Access:PDF Full Text
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Summary: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.
Physical Description:65 Pages
DOI:https://doi.org/10.17192/z2019.0457