Resistance of cancer stem cells and acquired genetic mutations are daunting challenges facing targeted cancer therapy, but the underlying mechanisms are not clear. This is best exampled by the tyrosine kinase inhibitor imatinib that effectively treats chronic myelogenous leukemia (CML) whereas resistance develops due to persistence of CML stem/progenitor cells and acquired mutations of BCR‐ABL. SIRT1 is a mammalian stress response gene homologous to yeast silent information regulator 2 (Sir2), a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase, and is involved in regulation of a variety of cellular functions including survival, glucose homeostasis and fat metabolism through deacetylating histones and non‐histone target proteins. Here we demonstrate that BCRABL transformation activates SIRT1 in hematopoietic stem/progenitor cells in both clinical CML patients and a CML‐like disease mouse model. Inhibition of SIRT1 by gene knockdown or pharmacological inhibitors suppresses CML cell proliferation and induces apoptosis in vitro. SIRT1 knockdown inhibits growth of CML tumor xenograft in immunodeficient mice. Homozygous knockout of SIRT1 gene inhibits BCR‐ABL transformation of mouse bone marrow cells and the development of a CML‐like myeloproliferative disease. We show that through deacetylation of Ku70, SIRT1 promotes BCR‐ABL mutations upon imatinib treatment and de novo genetic mutations upon DNA damage. Our results suggest an essential role of SIRT1 for BCR‐ABL oncogenic transformation and promoting cancer genome instability, and have implication for targeting SIRT1 to overcome resistance. These findings not only improve our understanding of SIRT1 functions in tumorigenesis, but also have translational implication for targeting SIRT1 for overcoming resistance in cancer treatment.

Citation Information: Cancer Res 2009;69(23 Suppl):B46.

©2009 American Association for Cancer Research
2009