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.

Keywords: :

• p53 restoration
• Arf
• apoptosis
• CML
• leukemia stem cells
• mouse models

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank César Cobaleda for helpful discussions and advice with colony formation assays; Esther Alonso for preparing tissue sections; Teresa Flores for help with pathology assessment and diagnosis; Jesús Pérez-Losada, Andrés Castellanos and members of the labs of D.M.-Z. and I.S.-G. for their continuous support. This work was funded by grants from the Spanish Ministry of Science and Innovation (MICINN) to D.M.-Z. (Refs. PI041418, PI082025), and to I.S.-G. (Refs CSD2007–0017 and SAF2009–08803). Partial funding was provided by Junta de Castilla y León to D.M.-Z. (Ref. CSI224A11–2), to I.S.-G. (Ref. CSI007A11–2) and to both (Group of Excellence Grant, GR15). All Spanish funding was co-sponsored by the European Union FEDER program. I.S.-G. is an API lab of the EuroSyStem project.