Guo Chen, Ran Qiuju, Sun Chun, Zhou Tingting, Yang Xi, Zhang Jizhou, Pang Shifeng, Xiao Yechen
Department of Biotechnology, Guangdong Medical University, Dongguan, China.
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China.
Front Pharmacol. 2021 Jan 29;11:632809. doi: 10.3389/fphar.2020.632809. eCollection 2020.
Chemotherapeutic patients with leukemia often relapse and produce drug resistance due to the existence of leukemia stem cells (LSCs). Fibroblast growth factor receptor 3 (FGFR3) signaling mediates the drug resistance of LSCs in chronic myeloid leukemia (CML). However, the function of FGFR3 in acute myeloid leukemia (AML) is less understood. Here, we identified that the loss of FGFR3 reprograms MLL-AF9 (MA)-driven murine AML cells into weakly pathogenic CD117-positive leukemia stem-like cells by activating the FGFR1-ERG signaling pathway. FGFR3 deletion significantly inhibits AML cells engraftment and extends the survival time of leukemic mice. FGFR3 deletion sharply decreased the expression of chemokines and the prolonged survival time in mice receiving FGFR3-deficient MA cells could be neutralized by overexpression of CCL3. Here we firstly found that FGFR3 had a novel regulatory mechanism for the stemness of LSCs in AML, and provided a promising anti-leukemia approach by interrupting FGFR3.
由于白血病干细胞（LSC）的存在，白血病化疗患者常出现复发并产生耐药性。成纤维细胞生长因子受体3（FGFR3）信号传导介导慢性粒细胞白血病（CML）中LSC的耐药性。然而，FGFR3在急性髓系白血病（AML）中的功能尚不清楚。在此，我们发现FGFR3的缺失通过激活FGFR1-ERG信号通路，将MLL-AF9（MA）驱动的小鼠AML细胞重编程为低致病性CD117阳性白血病干细胞样细胞。FGFR3缺失显著抑制AML细胞植入，并延长白血病小鼠的生存时间。FGFR3缺失显著降低趋化因子的表达，并且通过CCL3的过表达可以中和接受FGFR3缺陷型MA细胞的小鼠延长的生存时间。在此，我们首次发现FGFR3对AML中LSC的干性具有新的调控机制，并通过阻断FGFR3提供了一种有前景的抗白血病方法。
