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.

Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia / A. Garitano-Trojaola, A. Sancho, R. Gotz, P. Eiring, S. Walz, H. Jetani, J. Gil-Pulido, M.C. Da Vià, E. Teufel, N. Rhodes, L. Haertle, E. Arellano-Viera, R. Tibes, A. Rosenwald, L. Rasche, M. Hudecek, M. Sauer, J. Groll, H. Einsele, S. Kraus, M.K. Kortum. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 4:1(2021), pp. 799.1-799.14. [10.1038/s42003-021-02215-w]

Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

M.C. Da Vià;
2021

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.
Actin Cytoskeleton; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-bcl-2; Pyrones; Quinolines; Staurosporine; Sulfonamides; fms-Like Tyrosine Kinase 3; rac1 GTP-Binding Protein; Mutation
Settore MED/15 - Malattie del Sangue
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/892432
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