TitleChemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines.
Publication TypeJournal Article
Year of Publication2023
AuthorsIllangeswaran RStephen St, Jebanesan DZechariah, Sivakumar KKanimozhi, Vidhyadharan RThalayattu, Rajamani BM, Janet NBeryl, David E, Velayudhan SRamachandr, Mathews V, Balasubramanian P
JournalLeuk Res
Date Published2023 May
KeywordsAntineoplastic Agents, Arsenic Trioxide, Cell Line, Tumor, Cytarabine, Humans, Leukemia, Myeloid, Acute, Phenotype

Chemotherapy resistance leading to disease relapse is a significant barrier in treating acute myeloid leukemia (AML). Metabolic adaptations have been shown to contribute to therapy resistance. However, little is known about whether specific therapies cause specific metabolic changes. We established cytarabine-resistant (AraC-R) and Arsenic trioxide-resistant (ATO-R) AML cell lines, displaying distinct cell surface expression and cytogenetic abnormalities. Transcriptomic analysis revealed a significant difference in the expression profiles of ATO-R and AraC-R cells. Geneset enrichment analysis showed AraC-R cells rely on OXPHOS, while ATO-R cells on glycolysis. ATO-R cells were also enriched for stemness gene signatures, whereas AraC-R cells were not. The mito stress and glycolytic stress tests confirmed these findings. The distinct metabolic adaptation of AraC-R cells increased sensitivity to the OXPHOS inhibitor venetoclax. Cytarabine resistance was circumvented in AraC-R cells by combining Ven and AraC. In vivo, ATO-R cells showed increased repopulating potential, leading to aggressive leukemia compared to the parental and AraC-R. Overall, our study shows that different therapies can cause different metabolic changes and that these metabolic dependencies can be used to target chemotherapy-resistant AML.

Alternate JournalLeuk Res
PubMed ID36906941