SIRT1 regulates metabolism and leukemogenic potential in CML stem cells.

Abstract	Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for SIRT1 and downstream signaling mechanisms in altered mitochondrial respiration in CML LSCs.
Authors	Ajay Abraham, Shaowei Qiu, Balu K Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M Darley-Usmar, Ravi Bhatia
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 7 Pg. 2685-2701 (06 10 2019) ISSN: 1558-8238 [Electronic] United States
PMID	31180336 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Neoplasm Proteins Protein Kinase Inhibitors SIRT1 protein, human Sirt1 protein, mouse Sirtuin 1
Topics	Animals Drug Resistance, Neoplasm Gene Deletion Gene Expression Regulation, Enzymologic Gene Expression Regulation, Leukemic Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, genetics, pathology) Mice Mice, Transgenic Mitochondria (genetics, metabolism, pathology) Neoplasm Proteins (biosynthesis, genetics) Neoplastic Stem Cells (enzymology, pathology) Oxygen Consumption (genetics) Protein Kinase Inhibitors (pharmacology) Sirtuin 1 (biosynthesis, genetics)

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