Supporting data for "Metabolic rewiring in CD8+ T cell drives Venetoclax resistance in Acute Myeloid Leukemia"

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.