title: p53 restoration kills primitive leukemia cells in vivo and increases survival of leukemic mice.
abstract: Loss of p53 function is a common feature of human cancers and it is required for differentiated tumor cell maintenance; however, it is not known whether sustained inactivation of the p53 pathway is needed for cancer stem cell persistence. Chronic myeloid leukemia (CML) is caused by a chromosome translocation that generates the BCRABL oncogene encoding a constitutively active protein tyrosine kinase. The disease originates in a hematopoietic stem cell and is maintained by leukemic stem cells (LSCs). Treatment with specific tyrosine kinase inhibitors does not eliminate LSCs because they do not depend on the oncogene for survival. We have combined a switchable p53 knock-in mouse model, p53 (KI/KI) , with the well-characterized Sca1-BCRABLp210 CML transgenic model, to show that transient restoration of p53 slows disease progression and significantly extends the survival of leukemic animals, being the mechanism responsible for this effect, apoptotic death of primitive leukemia cells. In agreement with these in vivo findings, in vitro assays show that restoring p53 reduces hematopoietic colony formation by cells of leukemic animals. These results suggest that reestablishing p53 function may be a therapeutic strategy for the eradication of leukemic stem cells and to prevent disease progression.
authors.affiliation: Instituto de Biología Funcional y Genómica, CSIC/Universidad de Salamanca.
authors.forename: Talía
authors.initials: T
authors.lastname: Velasco-Hernández
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.forename: Dionisio
authors.initials: D
authors.lastname: Martin-Zanca
mesh_terms: D000483:Alleles; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D016922:Cellular Senescence; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D055879:Gene Knock-In Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D016044:Fusion Proteins, bcr-abl