2026-10-07T16:51:11Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33284166 2026-09-21T09:23:26Z category_24142 category_24631 category_24466 category_24616 portal_886 item_type_3 month_year_09_2026

Supporting data for "Metabolic rewiring in CD8+ T cell drives Venetoclax resistance in Acute Myeloid Leukemia" Xiaoyuan Zeng (13144275) Cell metabolism Tumour immunology Haematology Cellular immunology CD8+ cell cell metabolism regulations acute myeloid leukemia with myelodysplasia-related changes <p dir="ltr">Venetoclax (VEN), in combination with hypomethylating agent, has become the standard of care for unfit and elderly patients with acute myeloid leukemia (AML) but relapse is common. Mechanisms of drug resistance are thought to be intrinsic to leukemic cells. We reported a hitherto undescribed mechanism of venetoclax resistance (VR) pertinent to CD8⁺ T cells activity and identified hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cell receptor (TCR) signaling, as potential target that may overcome VR Combination of HPK1 inhibitor (HPK1i) and VEN synergistically activated CD8⁺ T cells, reduced leukemia burden and prolonged animal survival in an immunocompetent mouse model of AML. Single cell RNA-sequencing (scRNA-seq) and untargeted metabolomics showed that bone marrow (BM) CD8⁺ T cells at remission manifested increase in metabolic fitness characterized by increase in mitochondrial function, metabolic shift from glucose reliance to fatty acid oxidative phosphorylation (OXPHOS), and reduced oxidative stress. There was increase in Hsp70-mediated proteostasis and the T cells responses were mitigated by Hsp70 inhibitor. At relapse, these processes were reversed and there was evidence of defective maturation and reduced cytotoxicity in CD8⁺ T cell. Exogeneous nicotinamide riboside (NR) rewired mitochondrial metabolism and reduced oxidative stress in CD8⁺ T cells, resulting in their reactivation and improved treatment effects of HPK1i and VEN. Our findings underscored the significance of CD8⁺ T cells immunity in mediating VEN response and the subsequent relapse in AML via metabolic rewiring of mitochondria. HPK1i and NR may become important leads for future clinical studies of VEN based AML therapy.</p> 2026-09-21T09:23:26Z Dataset Dataset 10.25442/hku.33284166.v1 https://figshare.com/articles/dataset/Supporting_data_for_Metabolic_rewiring_in_CD8_T_cell_drives_Venetoclax_resistance_in_Acute_Myeloid_Leukemia_/33284166 CC BY-NC 4.0