Detalle Publicación

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

Autores: Garitano-Trojaola, Andoni; Sancho Erkizia, Ana; Goetz, Ralph; Eiring, Patrick; Walz, Susanne; Jetani, Hardikkumar; Gil-Pulido, Jesus; Da Via, Matteo Claudio; Teufel, Eva; Rhodes, Nadine; Haertle, Larissa; Arellano-Viera, Estibaliz; Tibes, Raoul; Rosenwald, Andreas; Rasche, Leo; Hudecek, Michael; Sauer, Markus; Groll, Juergen; Einsele, Hermann; Kraus, Sabrina; Kortuem, Martin K.
Título de la revista: COMMUNICATIONS BIOLOGY
ISSN: 2399-3642
Volumen: 4
Número: 1
Páginas: 799
Fecha de publicación: 2021
Resumen:
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. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatme