Adaptive Metabolic Response to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukemia Stem Cells

Tyrosine kinase inhibitors (TKI) are highly effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent CML stem cells persist as a source for recurrence. The effects of TKI treatment on CML stem cell metabolism, and the role of metabolic reprogramming in CML stem cell persistence after TKI treatment are not clear. Here we show that TKI treatment in a CML mouse model leads to acute inhibition of aerobic glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation (OXPHOS) in CML progenitor cells, but that these pathways are restored with continued TKI treatment. Single cell analysis reveals that primitive CML stem cell subpopulations characterized by lower OXPHOS, glycolysis, nucleotide metabolism, and MYC gene signatures are enriched after TKI treatment. TKI treatment initially results in broad inhibition of energy metabolism gene signatures, but continued treatment leads to metabolic reprogramming in persistent stem cells, with enhanced OXPHOS and MYC gene signatures. TKI treatment enhanced HIF-1 activity in quiescent CML stem cells, and addition of a HIF-1 inhibitor significantly depleted CML stem cells in TKI-treated mice. Our results identify mechanisms of metabolic adaptation in CML stem cells following TKI treatment, which can be targeted to deplete persistent quiescent CML stem cells. We studied changes in energy metabolism in CML stem and progenitor cells in response to TKI treatment using an inducible, transgenic SCL-tTA/BCR-ABL (BA) mouse model. In this model, tetracycline withdrawal leads to BCR-ABL expression in HSC and development of CML-like myeloproliferative disease. CML and normal mice were treated with the BCR-ABL TKI Nilotinib (50mg/kg daily by gavage) or vehicle. Bone marrow (BM) c-Kit+ cells were used for bioenergetics and metabolomics assays in order to have sufficient numbers of cells to conduct these analyses. However, this population is largely composed of progenitor cells and we therefore performed single cell gene expression analysis on BM Lin-FLT3-Sca-1+Kit+ (LSK) to study effects of TKI treatment on metabolism-related gene expression in primitive CML stem cells