Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China.
Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China.
Sci Rep. 2019 Aug 21;9(1):12209. doi: 10.1038/s41598-019-48687-z.
Chemokine ligand 12(CXCL12) mediates signaling through chemokine receptor 4(CXCR4), which is essential for the homing and maintenance of Hematopoietic stem cells (HSCs) in the bone marrow. FLT3-ITD mutations enhance cell migration toward CXCL12, providing a drug resistance mechanism underlying the poor effects of FLT3-ITD antagonists. However, the mechanism by which FLT3-ITD mutations regulate the CXCL12/CXCR4 axis remains unclear. We analyzed the relationship between CXCR4 expression and the FLT3-ITD mutation in 466 patients with de novo AML to clarify the effect of FLT3-ITD mutations on CXCR4 expression in patients with AML. Our results indicated a positive correlation between the FLT3-ITD mutant-type allelic ratio (FLT3-ITD MR) and the relative fluorescence intensity (RFI) of CXCR4 expression in patients with AML (r = 0.588, P ≤ 0.0001). Moreover, the levels of phospho(p)-STAT5, Pim-1 and CXCR4 proteins were positively correlated with the FLT3-ITD MR, and the mRNA levels of CXCR4 and Pim-1 which has been revealed as one of the first known target genes of STAT5, were upregulated with an increasing FLT3-ITD MR(P < 0.05). Therefore, FLT3-ITD mutations upregulate the expression of CXCR4 in patients with AML, and the downstream signaling intermediates STAT5 and Pim-1 are also involved in this phenomenon and subsequently contribute to chemotherapy resistance and disease relapse in patients with AML. However, the mechanism must be confirmed in further experiments. The combination of CXCR4 antagonists and FLT3 inhibitors may improve the sensitivity of AML cells to chemotherapy and overcome drug resistance.
趋化因子配体 12（CXCL12）通过趋化因子受体 4（CXCR4）介导信号转导，对于造血干细胞（HSCs）在骨髓中的归巢和维持至关重要。FLT3-ITD 突变增强了细胞对 CXCL12 的迁移，为 FLT3-ITD 拮抗剂效果不佳提供了一种耐药机制。然而，FLT3-ITD 突变调节 CXCL12/CXCR4 轴的机制尚不清楚。我们分析了 466 例初诊 AML 患者中 CXCR4 表达与 FLT3-ITD 突变之间的关系，以阐明 FLT3-ITD 突变对 AML 患者 CXCR4 表达的影响。我们的结果表明，FLT3-ITD 突变型等位基因比值（FLT3-ITD MR）与 AML 患者 CXCR4 表达的相对荧光强度（RFI）呈正相关（r=0.588，P≤0.0001）。此外，磷酸化（p）-STAT5、Pim-1 和 CXCR4 蛋白水平与 FLT3-ITD MR 呈正相关，而 CXCR4 和 Pim-1 的 mRNA 水平（已被揭示为 STAT5 的首批已知靶基因之一）随着 FLT3-ITD MR 的增加而上调（P<0.05）。因此，FLT3-ITD 突变上调了 AML 患者 CXCR4 的表达，下游信号转导中间物 STAT5 和 Pim-1 也参与了这一现象，进而导致 AML 患者化疗耐药和疾病复发。然而，该机制必须在进一步的实验中得到证实。CXCR4 拮抗剂与 FLT3 抑制剂的联合应用可能提高 AML 细胞对化疗的敏感性，克服耐药性。
