Blocking ETV6/RUNX1-induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia.

ABSTRACT: ETV6/RUNX1 (E/R) is the most common fusion gene in childhood acute lymphoblastic leukemia. It is responsible for the initiation of leukemia but also indispensable for disease maintenance and propagation, although its function in these latter processes is less clear. We therefore investigated the effects of the perceived p53 pathway alterations in model cell lines and primary leukemias and, in particular, how E/R upregulates MDM2, the predominant negative regulator of p53. We found that E/R transactivates MDM2 in both p53(+/+) and p53(-/-) HCT116 cells by binding to promoter-inherent RUNX1 motifs, which indicates that this activation occurs in a direct and p53-independent manner. Treatment of E/R-positive leukemic cell lines with Nutlin-3, a small molecule that inhibits the MDM2/p53 interac

SUBMITTER: Kaindl U 

PROVIDER: S-EPMC3948158 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature