Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance
Abstract Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01515-w |
| _version_ | 1797784766307631104 |
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| author | Ghizlane Choukrani Nienke Visser Natasha Ustyanovska Avtenyuk Mirjam Olthuis Glenn Marsman Emanuele Ammatuna Harm Jan Lourens Toshiro Niki Gerwin Huls Edwin Bremer Valerie R. Wiersma |
| author_facet | Ghizlane Choukrani Nienke Visser Natasha Ustyanovska Avtenyuk Mirjam Olthuis Glenn Marsman Emanuele Ammatuna Harm Jan Lourens Toshiro Niki Gerwin Huls Edwin Bremer Valerie R. Wiersma |
| author_sort | Ghizlane Choukrani |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but was negatively associated with autophagic flux. Importantly, both AraC-sensitive and -resistant AML cell lines, as well as AML patient samples, were sensitive to single-agent treatment with Gal-9. Additionally, Gal-9 potentiated the cytotoxic effect of DNA demethylase inhibitor Azacytidine (Aza), a drug that is clinically used for patients that are not eligible for intensive AraC treatment. Thus, Gal-9 is a potential therapeutic agent for the treatment of AML, including AraC-resistant AML, by inducing caspase-independent cell death. |
| first_indexed | 2024-03-13T00:44:34Z |
| format | Article |
| id | doaj.art-744707850025474188f77817ec125057 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-13T00:44:34Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-744707850025474188f77817ec1250572023-07-09T11:06:15ZengNature Publishing GroupCell Death Discovery2058-77162023-07-019111210.1038/s41420-023-01515-wGalectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistanceGhizlane Choukrani0Nienke Visser1Natasha Ustyanovska Avtenyuk2Mirjam Olthuis3Glenn Marsman4Emanuele Ammatuna5Harm Jan Lourens6Toshiro Niki7Gerwin Huls8Edwin Bremer9Valerie R. Wiersma10Department of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Immunology, Kagawa UniversityDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenDepartment of Hematology, University Medical Center Groningen, University of GroningenAbstract Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but was negatively associated with autophagic flux. Importantly, both AraC-sensitive and -resistant AML cell lines, as well as AML patient samples, were sensitive to single-agent treatment with Gal-9. Additionally, Gal-9 potentiated the cytotoxic effect of DNA demethylase inhibitor Azacytidine (Aza), a drug that is clinically used for patients that are not eligible for intensive AraC treatment. Thus, Gal-9 is a potential therapeutic agent for the treatment of AML, including AraC-resistant AML, by inducing caspase-independent cell death.https://doi.org/10.1038/s41420-023-01515-w |
| spellingShingle | Ghizlane Choukrani Nienke Visser Natasha Ustyanovska Avtenyuk Mirjam Olthuis Glenn Marsman Emanuele Ammatuna Harm Jan Lourens Toshiro Niki Gerwin Huls Edwin Bremer Valerie R. Wiersma Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance Cell Death Discovery |
| title | Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| title_full | Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| title_fullStr | Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| title_full_unstemmed | Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| title_short | Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| title_sort | galectin 9 has non apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance |
| url | https://doi.org/10.1038/s41420-023-01515-w |
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