Targeting homologous recombination repair in BCR/ABL1-positive cells using PARP inhibitor

Abstract

Abstract BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit the growth of CML and Ph1-ALL cells with downregulated BRCA1 expression. Inhibition of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. Here, we demonstrate that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. Inhibition of leukemogenesis in BCR/ABL1-positive cells was the result of a combination of the direct cytotoxic effects of olaparib and reduced maintenance of BCR/ABL1-positive stem cells. Interferon was used as a first-line therapy for CML.Activation of the cGAS/STING pathway was also observed upon PARP inhibition. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, PARPi could be combined with TKIs to induce CML cell death more effectively.