title: SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.
abstract: BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.forename: M
authors.initials: M
authors.lastname: Roth
authors.forename: J M
authors.initials: JM
authors.lastname: Stark
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.forename: W Y
authors.initials: WY
authors.lastname: Chen
mesh_terms: D001549:Benzamides; D045744:Cell Line, Tumor; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000627:therapeutic use; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C447939:SIRT1 protein, human; D056564:Sirtuin 1