Abstract
Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.
[Display omitted]
•DLBCLs expressing LMO2 protein have deficient homologous recombination DNA repair•LMO2 interacts with and requires 53BP1 to inhibit homologous recombination•LMO2 expression sensitizes tumor cells to PARP1/2 inhibitors (PARPi)•PARPi and chemotherapy synergistically inhibit the growth of LMO2-positive tumors
Parvin et al. show that LMO2 inhibits BRCA1 recruitment to DNA double-strand breaks (DSB) by interacting with 53BP1. Thus, diffuse large B cell lymphomas expressing LMO2 are functionally deficient in homologous recombination-mediated DSB repair and are sensitive to poly(ADP-ribose) polymerase inhibitors.
