Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner
Abstract Background Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We previously discovered that heme oxygenase 1 (HO1) is crucial for chemoresistance in AML, but the detailed molecular mechanism of that remains unclear. Methods RNA sequencing was conducted to asse...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-025-03757-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849734698085908480 |
|---|---|
| author | Tianzhuo Zhang Danna Wei Yun Zhan Zhengmei Long Tingting Lu Peng Zhao Rui Gao Qian Kang Luxin Zhang Min Liu Xueying Yang Jishi Wang |
| author_facet | Tianzhuo Zhang Danna Wei Yun Zhan Zhengmei Long Tingting Lu Peng Zhao Rui Gao Qian Kang Luxin Zhang Min Liu Xueying Yang Jishi Wang |
| author_sort | Tianzhuo Zhang |
| collection | DOAJ |
| description | Abstract Background Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We previously discovered that heme oxygenase 1 (HO1) is crucial for chemoresistance in AML, but the detailed molecular mechanism of that remains unclear. Methods RNA sequencing was conducted to assess transcriptomic changes in three pairs of AML cells after regulating the expression of HO1. The molecular mechanism by which HO1 induces gilteritinib resistance in FLT3-ITD (FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD)) AML was evaluated by quantitative real-time PCR (qRT-PCR), CCK-8, flow cytometry, and western blotting. FLT3-ITD AML mouse models were established to investigate the effects of HO1 expression on gilteritinib resistance in vivo. Results In these three pairs of AML cells, we discovered that HO1-mediated drug resistance is connected to the interleukin-4-mediated signaling pathway (specifically STAT6) only in MV4-11 cells with the FLT3-ITD mutation. Further findings revealed that HO1 overexpression confers gilteritinib resistance in FLT3-ITD AML cell lines and primary individual specimens. While suppression of HO1 sensitized FLT3-ITD AML cell lines and primary individual specimens to gilteritinib. Mechanistically, western blotting and flow cytometry confirmed that HO1-mediated gilteritinib resistance is related to STAT6 phosphorylation in FLT3-ITD AML cell lines and primary individual specimens. Moreover, tumor-bearing mice were employed to determine that HO1 overexpression conferred gilteritinib resistance in vivo. Conclusions Collectively, these studies illustrate that HO1 may act as a successful treatment target for gilteritinib-resistant FLT3-ITD AML patients. |
| format | Article |
| id | doaj-art-86e7c3346d2e45e2bddccf60013069fc |
| institution | DOAJ |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-86e7c3346d2e45e2bddccf60013069fc2025-08-20T03:07:44ZengBMCCancer Cell International1475-28672025-04-0125111210.1186/s12935-025-03757-3Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent mannerTianzhuo Zhang0Danna Wei1Yun Zhan2Zhengmei Long3Tingting Lu4Peng Zhao5Rui Gao6Qian Kang7Luxin Zhang8Min Liu9Xueying Yang10Jishi Wang11Department of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Pediatric Hematology, Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s HospitalDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityCenter for Clinical Laboratories, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, Affiliated Hospital of Guizhou Medical UniversityAbstract Background Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We previously discovered that heme oxygenase 1 (HO1) is crucial for chemoresistance in AML, but the detailed molecular mechanism of that remains unclear. Methods RNA sequencing was conducted to assess transcriptomic changes in three pairs of AML cells after regulating the expression of HO1. The molecular mechanism by which HO1 induces gilteritinib resistance in FLT3-ITD (FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD)) AML was evaluated by quantitative real-time PCR (qRT-PCR), CCK-8, flow cytometry, and western blotting. FLT3-ITD AML mouse models were established to investigate the effects of HO1 expression on gilteritinib resistance in vivo. Results In these three pairs of AML cells, we discovered that HO1-mediated drug resistance is connected to the interleukin-4-mediated signaling pathway (specifically STAT6) only in MV4-11 cells with the FLT3-ITD mutation. Further findings revealed that HO1 overexpression confers gilteritinib resistance in FLT3-ITD AML cell lines and primary individual specimens. While suppression of HO1 sensitized FLT3-ITD AML cell lines and primary individual specimens to gilteritinib. Mechanistically, western blotting and flow cytometry confirmed that HO1-mediated gilteritinib resistance is related to STAT6 phosphorylation in FLT3-ITD AML cell lines and primary individual specimens. Moreover, tumor-bearing mice were employed to determine that HO1 overexpression conferred gilteritinib resistance in vivo. Conclusions Collectively, these studies illustrate that HO1 may act as a successful treatment target for gilteritinib-resistant FLT3-ITD AML patients.https://doi.org/10.1186/s12935-025-03757-3Heme Oxygenase 1Acute myeloid leukemiaFLT3-ITD mutationGilteritinib resistanceSTAT6 |
| spellingShingle | Tianzhuo Zhang Danna Wei Yun Zhan Zhengmei Long Tingting Lu Peng Zhao Rui Gao Qian Kang Luxin Zhang Min Liu Xueying Yang Jishi Wang Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner Cancer Cell International Heme Oxygenase 1 Acute myeloid leukemia FLT3-ITD mutation Gilteritinib resistance STAT6 |
| title | Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner |
| title_full | Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner |
| title_fullStr | Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner |
| title_full_unstemmed | Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner |
| title_short | Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner |
| title_sort | heme oxygenase 1 confers gilteritinib resistance in flt3 itd acute myeloid leukemia in a stat6 dependent manner |
| topic | Heme Oxygenase 1 Acute myeloid leukemia FLT3-ITD mutation Gilteritinib resistance STAT6 |
| url | https://doi.org/10.1186/s12935-025-03757-3 |
| work_keys_str_mv | AT tianzhuozhang hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT dannawei hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT yunzhan hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT zhengmeilong hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT tingtinglu hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT pengzhao hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT ruigao hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT qiankang hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT luxinzhang hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT minliu hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT xueyingyang hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner AT jishiwang hemeoxygenase1confersgilteritinibresistanceinflt3itdacutemyeloidleukemiainastat6dependentmanner |