Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance

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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

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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.

Originele taal-2English
Artikelnummer228
Aantal pagina's12
TijdschriftCell Death and Discovery
Volume9
DOI's
StatusPublished - 6-jul.-2023

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