Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability.
Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability.
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DOI：
10.3390/biomedicines10051038
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发表时间：
2022-04-30
期刊：
影响因子：
4.7
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中科院分区：
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--
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疾病复发是fms样酪氨酸激酶3 （FLT3）突变的急性髓性白血病（AML）治疗失败的常见原因。在本研究中，为了确定在gilteritinib （GILT，一种第二代酪氨酸激酶抑制剂（TKI））治疗后FLT3突变白血病细胞（母细胞）存活和增殖的治疗靶点，我们进行了细胞因子释放的蛋白质组学筛选和体外/离体研究，以研究其相关的信号通路和转录调控。在这里，我们报告了巨噬细胞迁移抑制因子（MIF）在gilt处理的细胞上清液中与未处理的对照组相比显着增加。此外，发现存活的经gilt处理的细胞表现出更高的CXCR2基因和蛋白表达，CXCR2基因和蛋白是MIF和促炎细胞因子的常见受体。将外源性MIF补充到gilt处理的母细胞中，发现一组CD44High+细胞可能是导致复发的原因。此外，我们在gilt处理后发现了高度激活的非经典NFKB2通路。NFKB2的siRNA瞬间敲低可显著降低MIF、CXCR2和CXCL5的基因表达。最后，对AML患者样本的体外治疗表明，NFKB家族药物抑制剂与GILT联合可有效抑制原代细胞分泌促肿瘤细胞因子，如CXCL1/5/8。总之，我们提供了第一个证据，证明靶向治疗激活的代偿通路，如NFKB2-MIF/CXCLs-CXCR2轴可能是一种新的治疗策略，可以克服tki耐药并有效治疗FLT3突变的AML患者。
Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.
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