Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
Department of Functional Materials in Medicine and Dentistry and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany.
Commun Biol. 2021 Jun 25;4(1):799. doi: 10.1038/s42003-021-02215-w.
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.
FMS 样酪氨酸激酶 3 内部串联重复（FLT3-ITD）的存在是急性髓系白血病（AML）中最常见的突变之一，与预后不良相关。FLT3 抑制剂，如米哚妥林，临床上被用于治疗，但未能完全消除 FLT3-ITD+AML。本研究提出了一个新的观点，强调了 RAC1 依赖性肌动蛋白细胞骨架重塑对 AML 中米哚妥林耐药性的影响。RAC1 的过度激活通过肌动蛋白聚合的正调节剂 N-WASP 的过度磷酸化和抗凋亡的 BCL-2 导致耐药性。RAC1/N-WASP 通过 ARP2/3 复合物的激活，增加肌动蛋白丝的数量、细胞刚性和与间充质基质细胞（MSCs）的粘附力，被确定为耐药性的生物标志物。在米哚妥林耐药的 AML 细胞系和原代样本中，米哚妥林、BCL-2 抑制剂 venetoclax 和 RAC1 抑制剂 Eht1864 的联合使用可以克服米哚妥林耐药性，为消除 FLT3-ITD+AML 的潜在新治疗方法提供了首个证据。
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