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

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

PROVIDER: PRJNA854901 | ENA |

REPOSITORIES: ENA

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

Project description: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.

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Imatinib and Nilotinib induced molecular changes in Philadelphia chromosome-positive Chronic Myelogenous Leukemia

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Transcription profiling of four mouse cell lines with mutations in the oncogenic tyrosine kinase gene BCR-Abl

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Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

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Project description:Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells. It is a target of tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment. Flt3 and its ligand (Flt3L) are expressed in the heart and cardiac side effects occur under Flt3-targeting TKIs. Whether Flt3/Flt3L also regulate cardiac progenitor cells (CPCs), however, is not known. The cardiac side population (SP) is a pool of heterogenous CPCs that can give rise to all cardiac lineages, hence contributing to cardiovascular homeostasis. Here we show that SP-CPCs produce and are responsive to Flt3L. Compared to wild-type, SP-CPCs from flt3L-/- mice are less abundant, with less contribution of CD45-CD34+ cells, and lower expression of gene sets related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing and compared to wild-type, flt3L-/- Sca1+CD31- SP-CPCs show increased proliferation and less vasculogenic commitment, but differentiation can be induced in the presence of receptor tyrosine kinase-activating growth factors. The observed differences are associated with decreased microvascularisation and global systolic function of flt3L-/- hearts. Thus, Flt3 contributes to a receptor tyrosine kinase signature necessary for the maintenance and functionality of SP-CPCs. These findings have potential implications regarding cardiovascular side effects observed under TKI therapy.

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