LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

Cancer Cell. 2019 Sep 16;36(3):237-249.e6. doi: 10.1016/j.ccell.2019.07.007. Epub 2019 Aug 22.

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.

Keywords: 53BP1; BRCA1; DNA damage; LMO2; PARP; R-CHOP; acute lymphoblastic leukemia; diffuse large B cell lymphoma (DLBCL); homologous recombination; olaparib; synthetic lethality.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • BRCA1 Protein / metabolism
  • Biopsy
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded / drug effects
  • Drug Synergism
  • Humans
  • LIM Domain Proteins / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Palatine Tonsil / pathology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Poly(ADP-ribose) Polymerases / metabolism
  • Primary Cell Culture
  • Proto-Oncogene Proteins / metabolism*
  • Recombinational DNA Repair / drug effects*
  • Recombinational DNA Repair / genetics
  • Synthetic Lethal Mutations / drug effects*
  • Tumor Suppressor p53-Binding Protein 1
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • LIM Domain Proteins
  • LMO2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • PARP1 protein, human
  • PARP2 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases