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.
Highlights
The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-internal tandem duplications (ITDs)) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis
We hypothesized that FLT3 receptor phosphorylation and glycosylation, which have been associated with FLT3 inhibitor resistance, may induce related C3 botulinum toxin substrate 1 (RAC1) hyperactivation, which deregulates of actin dynamics and the antiapoptotic BCL2 family and may confer midostaurin resistance in FLT3mutant AML
To study the role of RAC1-regulated cellular processes in response to FLT3 inhibitors, we developed midostaurin-resistant AML cell lines from the FLT3-ITD homozygous and heterozygous AML cell lines MV4-11 and MOLM-13, respectively
Summary
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. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in ~30% of AML cases, with internal tandem duplications (ITDs) being the most common type of mutation These mutations lead to constitutive autophosphorylation of the FLT3 receptor; growth factor signaling pathways are activated. Profilin-1 (PFN1), which binds to N-WASP or WAVE proteins, can accelerate actin polymerization[14] Deregulation of this process through increasing the number of actin filaments and cell stiffness enhances the invasiveness and therapy resistance in solid tumor[15,16]. We hypothesized that FLT3 receptor phosphorylation and glycosylation, which have been associated with FLT3 inhibitor resistance, may induce RAC1 hyperactivation, which deregulates of actin dynamics and the antiapoptotic BCL2 family and may confer midostaurin resistance in FLT3mutant AML
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