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A bstract   Leukemia stem cells (LSCs) of chronic myeloid leukemia (CML) are refractory to tyrosine kinase inhibitor treatment, persist in the residual disease, and are important source for disease recurrence. Better understanding CML LSCs will help devise new strategies to eradicate these cells. The BALB/c mouse model of CML using retroviral bone marrow transduction and transplantation is a widely used mouse model system for CML, but LSCs in this model are poorly characterized. Here, we show that lineage negative CD150 −  side population (CD150 − SP), but not CD150 + SP, are CML LSCs in this model, although both CD150 − SP and CD150 + SP cells are enriched for long‐term hematopoietic stem cells in normal BALB/c mice. We previously showed that BCR‐ABL transformation activates protein lysine deacetylase SIRT1 and inhibition of SIRT1 sensitizes CML stem/progenitor cells to tyrosine kinase inhibitors by acetylating and activating p53. In this study, we demonstrate that SIRT1 homozygous knockout substantially reduces CD150 − SP CML LSCs, and compromises the maintenance of CML LSCs in the BALB/c model. We identified several molecular alterations in CD150 − SP LSCs that included the elevated expression of cyclin‐dependent kinase Cdk6 facilitating LSC activation and significantly reduced p53 expression. SIRT1 knockout suppressed Cdk6 expression and likely increases p53 protein functions through deacetylation without increasing its expression. Our results shed novel insight into CML LSCs and support a crucial role of SIRT1 in CML LSCs. Our study also provides a novel means for assessing new agents to eradicate CML LSCs. S tem  C ells   2015;33:3437–3451

CD 150 − Side Population Defines Leukemia Stem Cells in a BALB /c Mouse Model of CML and Is Depleted by Genetic Loss of SIRT1