GSE103638 Loss of p53 tumor suppressive function drives chemotherapy resistance in relapsed childhood B-cell precursor ALL

Contributors : Binbing S Zhou ; Renate Kirschner-Schwabe ; Fan Yang ; Malwine J Pogodzinski ; Lijuan Du ; Huiying Sun ; Liang Zhang ; Jana Hof ; Yonggong Zhai ; Cornelia Eckert ; Min LuSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensResistance to chemotherapy remains a challenge in the treatment of relapsed childhood acute lymphoblastic leukemia (ALL). Using a German B-cell precursor (BCP) ALL relapse cohort, we found that TP53 hot spot mutations, different from non-hot spot mutations but similar to indel and splice site mutations, are particularly associated with on-treatment relapse and non-response to chemotherapy in childhood BCP-ALL. Utilizing a CRISPR/Cas9 mediated TP53 knockout and re-expression BCP-ALL cell system, we demonstrated that replacing wild-type p53 with hot spot mutants causes resistance to multiple chemotherapy drugs. Topoisomerase II inhibitor induced DNA double strand breaks (DSBs), but failed to induce cell cycle arrest and apoptosis in cells expressing p53 hot spot mutants. The ChIP-seq results from BCP-ALL cells showed that p53 hot spot mutants are deficient in binding to the p53 ’s consensus element, including the regulation elements in the promoter regions of CDKN1A and pro-apoptotic genes. Mutant p53 reactivator PRIMA-1 rescued the induction of p21 and PUMA in TP53 hot spot mutation cells and reversed their resistance to idarubicin. These findings suggest loss of p53 tu mor suppressive...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research