Department of Biotechnology, Guangdong Medical University, Dongguan, China; Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China.
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China.
Transplant Cell Ther. 2021 Jan;27(1):45.e1-45.e10. doi: 10.1016/j.bbmt.2020.09.019. Epub 2020 Sep 20.
Patients with chemotherapy or radiation therapy often generate anemia and low immunity due to the therapy-induced bone marrow (BM) suppression. To enhance hematopoietic regeneration during the therapy-induced BM suppression urgently need to be solved. Fibroblast growth factors (FGFs) play important regulatory roles in hematopoietic stem and progenitor cell (HSPC) expansion in vitro and in vivo by the FGF receptor (FGFR1-4)-mediated signaling pathway. FGFR3 is an important member of the FGFR family, and its regulatory function in hematopoiesis is largely unknown. Using knockout (KO) mice of FGFR3, we found that loss of FGFR3 does not affect HSPC functions or lineage differentiation during steady-state hematopoiesis, but FGFR3 deletion accelerates HSPC expansion and hematopoiesis recovery via a cell-autonomous manner under 5-fluorouracil-induced BM suppression. Our results showed that FGFR3 inactivation accelerates BM suppression-induced HSPC expansion by upregulating FGFR1 and its downstream transcriptional factor, ELK, which regulates the expression of the cyclin D1 gene at the level of transcription. Further studies confirmed that loss of FGFR3 in hematopoietic cells inhibits in vivo leukemogenesis under BM suppression. Our data found a novel hematopoietic regulatory mechanism by which FGFR3 deletion promotes HSPC expansion under BM suppression and also provided a promising approach to enhance antileukemia and hematopoietic regeneration by inhibiting FGFR3 functions in HSPCs combined with leukemic chemotherapy.
患有化疗或放疗的患者常因治疗诱导的骨髓（BM）抑制而产生贫血和免疫力低下。为了在治疗诱导的 BM 抑制期间增强造血再生，迫切需要解决这个问题。成纤维细胞生长因子（FGFs）通过 FGF 受体（FGFR1-4）介导的信号通路在体外和体内对造血干细胞和祖细胞（HSPC）的扩增发挥重要的调节作用。FGFR3 是 FGFR 家族的重要成员，其在造血中的调节功能在很大程度上尚不清楚。利用 FGFR3 敲除（KO）小鼠，我们发现 FGFR3 的缺失并不影响 HSPC 功能或在稳态造血期间的谱系分化，但 FGFR3 缺失通过自主方式加速 HSPC 扩增和造血恢复，在 5-氟尿嘧啶诱导的 BM 抑制下。我们的研究结果表明，FGFR3 的失活通过上调 FGFR1 及其下游转录因子 ELK 加速 BM 抑制诱导的 HSPC 扩增，ELK 调节 cyclin D1 基因的表达在转录水平上。进一步的研究证实，造血细胞中 FGFR3 的缺失抑制了 BM 抑制下体内白血病的发生。我们的数据发现了一种新的造血调节机制，即 FGFR3 的缺失在 BM 抑制下促进 HSPC 扩增，并提供了一种有前途的方法，通过抑制 HSPC 中的 FGFR3 功能并结合白血病化疗来增强抗白血病和造血再生。
