文献类型：期刊文献

英文题名：Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia

作者：Zhou, Qi[1];Guan, Yongyu[2];Zhao, Pingping[1];Chu, Huiyuan[3];Xi, Yaming[1,4]

第一作者：Zhou, Qi

通信作者：Xi, YM[1]

机构：[1]Lanzhou Univ, Clin Med Coll 1, Lanzhou 730000, Peoples R China;[2]Gansu Prov Maternal & Child Hlth Care Hosp, Clin Lab, Lanzhou 730000, Peoples R China;[3]Gansu Univ Tradit Chinese Med, Sch Publ Hlth, Lanzhou 730000, Peoples R China;[4]Lanzhou Univ, Hosp 1, Dept Hematol, First Dong Gang Xi Rd, Lanzhou, Gansu, Peoples R China

第一机构：Lanzhou Univ, Clin Med Coll 1, Lanzhou 730000, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Hosp 1, Dept Hematol, First Dong Gang Xi Rd, Lanzhou, Gansu, Peoples R China.

年份：2025

卷号：52

外文期刊名：TRANSLATIONAL ONCOLOGY

收录：;Scopus(收录号：2-s2.0-85214824735);WOS:【SCI-EXPANDED(收录号:WOS:001414071600001)】；

语种：英文

外文关键词：Acute myeloid leukemia; FLT3-ITD; Gilteritinib; GSK-J4; Combination therapy

摘要：Gilteritinib treats acute myeloid leukemia (AML) with the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Dysregulation of histone modification affects the genesis and progression of AML. Strategies targeting key histone regulators have not been applied to the treatment of AML. Lysine demethylase 6B (KDM6B) is dysregulated in a variety of cancers and regulates the expression of oncogenes, which has potential in anticancer therapy. We explored whether GSK-J4 (an inhibitor of the demethylase KDM6B) has an anti-leukemic effect in the gilteritinib treatment of FLT3-ITD+ AML and the effect of gilteritinib combined with GSK-J4 in leukemia. In our study, we evaluated the anti-leukemic effect of GSK-J4 in gilteritinib therapy through in vitro and in vivo experiments. The results revealed that the combined treatment of gilteritinib and GSK-J4 has greater anti-proliferation and pro-apoptosis effects than gilteritinib alone. Gilteritinib and GSK-J4 performed synergistically to arrest the cell cycle. Gilteritinib mainly induces cell cycle phase arrest at the S or G0/G1, and GSK-J4 inhibits the cell cycle progression in the S phase and reduces cell viability by reducing the expression of key regulatory factors from the G1 phase to the S phase. At the same time, GSK-J4 enhances the expression of apoptosis-related proteins (Bax and cleavage caspase-9). In addition, gilteritinib or GSK-J4 monotherapy increases reactive oxygen species (ROS) production, and the combination has a synergistic effect, accelerating leukemic cell death. Our study provides proof that the combined therapy of gilteritinib and GSK-J4 has a synergistic antileukemic effect on FLT3-ITD+ AML.