Impact of p53 Target Genes on Drug Resistance in TP53-Mutated B-Cell Precursor Acute Lymphoblastic Leukemia.

Abstract

TP53 mutations are linked to poor prognoses in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), indicating that specific p53 target genes may contribute to drug resistance. Although the impact of specific genetic alterations on drug sensitivity has been reported in BCP-ALL, the effects of TP53 mutations on sensitivity to individual agents remain poorly defined in the clinical setting because of the use of combination chemotherapy regimens. In the present study, we addressed this issue through two complementary analyses using a large panel of BCP-ALL cell lines. Initially, 30 cell lines harboring TP53 mutations demonstrated significantly greater resistance to daunorubicin (DNR), mafosfamide (MAF; an active analog of cyclophosphamide), 6-mercaptopurine (6-MP), and prednisolone compared to 46 cell lines without mutations. Second, 11 CRISPR/Cas9-mediated TP53-knockout sublines derived from cell lines with wild-type TP53 recapitulated resistance to DNR, MAF, and 6-MP, as well as to vincristine (VCR) and cytarabine (Ara-C). Consistent with these findings, re-evaluation of genome-wide CRISPR screening datasets revealed significant enrichment of TP53 gRNAs in cells treated with DNR, MAF, 6-MP, Ara-C, and VCR. Furthermore, transcriptomic and proteomic analyses of p53 target genes in the two cell line models, along with re-evaluation of genome-wide CRISPR screening datasets, identified BAX, BBC3, and FDXR as key p53 target genes associated with multidrug resistance. These results highlight the potential value of targeting these p53 downstream pathways to improve outcomes in TP53-mutated BCP-ALL cases.