Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
Garitano-Trojaola A, Sancho A, Goetz R, Eiring P, Walz S, Jetani H, Gil-Pulido J, Da Via MC, Teufel E, Rhodes N, Haertle L, Arellano-Viera E, Tibes R, Rosenwald A, Rasche L, Hudecek M, Sauer M, Groll J, Einsele H, Kraus S, Kortuem MK (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 4
Pages Range: 799-
Journal Issue: 1
DOI: 10.1038/s42003-021-02215-w
Abstract
The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.
Involved external institutions
Institut für Molekulare Biologie gGmbH / Institute of Molecular Biology (IMB)
Germany (DE)
Universitätsklinikum Würzburg
Germany (DE)
Julius-Maximilians-Universität Würzburg
Germany (DE)
Germany (DE)
Universitätsklinikum Würzburg
Germany (DE)
Julius-Maximilians-Universität Würzburg
Germany (DE)
How to cite
APA:
Garitano-Trojaola, A., Sancho, A., Goetz, R., Eiring, P., Walz, S., Jetani, H.,... Kortuem, M.K. (2021). Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia. Communications Biology, 4(1), 799-. https://doi.org/10.1038/s42003-021-02215-w
MLA:
Garitano-Trojaola, Andoni, et al. "Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia." Communications Biology 4.1 (2021): 799-.
BibTeX: Download