PARP1 is differentially expressed in BCR-ABL p190+ ALL patient samples and targeting PARP inhibition induces cell death comparable to that of tyrosine- kinase golden standard in pre-clinical models

Abstract

Abstract Detection of t(9;22), and consequent BCR-ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR-ABL p190 + ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current golden-standard in medical care. We characterized cytostatic profiles, induced cell death and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190 + patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in the clinical practice.