Kannan Sankaranarayan, Irwin Mary E, Herbrich Shelley M, Cheng Tiewei, Patterson LaNisha L, Aitken Marisa J L, Bhalla Kapil, You M James, Konopleva Marina, Zweidler-McKay Patrick A, Chandra Joya
Department of Pediatrics Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Antioxidants (Basel). 2022 Apr 5;11(4):717. doi: 10.3390/antiox11040717.
Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2-related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated in AML resistance. Here, we demonstrate that HO-1 is elevated in FLT3-ITD-bearing cells compared to FLT3-wild type (WT). Transient knockdown or inhibitor-based suppression of HO-1 enhances vulnerability to the TKI, quizartinib, in both TKI-resistant and sensitive primary AML and cell line models. NRF2 suppression (genetically or pharmacologically using brusatol) results in decreased HO-1, suggesting that TKI-resistance is dependent on an active NRF2-driven pathway. In AML-patient derived xenograft (PDX) models, brusatol, in combination with daunorubicin, reduces leukemia burden and prolongs survival. Cumulatively, these data encourage further development of brusatol and NRF2 inhibition as components of combination therapy for refractory AML.
急性髓系白血病（AML）是一种分子异质性血液系统恶性肿瘤，最常见的突变之一是Fms样酪氨酸激酶受体3（FLT3）近膜结构域的内部串联重复（ITD）。尽管已经开发出针对FLT3的酪氨酸激酶抑制剂（TKI），但复发和耐药问题仍然存在，需要改进治疗策略。在患者样本和细胞系中，FLT3-ITD都会提高活性氧（ROS）水平并引发抗氧化反应，这与AML广泛的化疗耐药性有关。NF-E2相关因子2（NRF2）是一种转录因子，可调节抗氧化反应，包括血红素加氧酶-1（HO-1），这是一种与AML耐药有关的热休克蛋白。在此，我们证明与FLT3野生型（WT）细胞相比，携带FLT3-ITD的细胞中HO-1水平升高。在TKI耐药和敏感的原发性AML及细胞系模型中，短暂敲低或基于抑制剂抑制HO-1均可增强对TKI奎扎替尼的敏感性。抑制NRF2（通过基因手段或使用布沙替尼进行药理学抑制）会导致HO-1水平降低，这表明TKI耐药性依赖于活跃的NRF2驱动途径。在AML患者来源的异种移植（PDX）模型中，布沙替尼与柔红霉素联合使用可减轻白血病负担并延长生存期。总体而言，这些数据鼓励进一步开发布沙替尼和抑制NRF2，作为难治性AML联合治疗的组成部分。
