Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia
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...
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Elsevier
2025-02-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325000026 |
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| author | Qi Zhou Yongyu Guan Pingping Zhao Huiyuan Chu Yaming Xi |
| author_facet | Qi Zhou Yongyu Guan Pingping Zhao Huiyuan Chu Yaming Xi |
| author_sort | Qi Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9502c8129cec4baca2905cdc2000fde2 |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-9502c8129cec4baca2905cdc2000fde22025-01-22T05:41:34ZengElsevierTranslational Oncology1936-52332025-02-0152102271Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemiaQi Zhou0Yongyu Guan1Pingping Zhao2Huiyuan Chu3Yaming Xi4The First Clinical Medical College of Lanzhou University, Lanzhou 730000, ChinaClinical laboratory, Gansu Provincial Maternal and Child Health Care Hospital, Lanzhou 730000, ChinaThe First Clinical Medical College of Lanzhou University, Lanzhou 730000, ChinaSchool of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, ChinaThe First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; Department of Hematology, The First Hospital of Lanzhou University, Lanzhou 730000, China; Corresponding author at: Department of Hematology, The First Hospital of Lanzhou University, The First Dong Gang Xi Road, Lanzhou, Gansu Province, China.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.http://www.sciencedirect.com/science/article/pii/S1936523325000026Acute myeloid leukemiaFLT3-ITDGilteritinibGSK-J4Combination therapy |
| spellingShingle | Qi Zhou Yongyu Guan Pingping Zhao Huiyuan Chu Yaming Xi Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia Translational Oncology Acute myeloid leukemia FLT3-ITD Gilteritinib GSK-J4 Combination therapy |
| title | Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia |
| title_full | Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia |
| title_fullStr | Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia |
| title_full_unstemmed | Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia |
| title_short | Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia |
| title_sort | combined anti leukemic effect of gilteritinib and gsk j4 in flt3 itd acute myeloid leukemia |
| topic | Acute myeloid leukemia FLT3-ITD Gilteritinib GSK-J4 Combination therapy |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325000026 |
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