LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

Salma Parvin, Ariel Ramirez-Labrada, Shlomzion Aumann, Xiao Qing Lu, Natalia Weich, Gabriel Santiago, Elena M. Cortizas, Eden Sharabi, Yu Zhang, Isidro Sanchez-Garcia, Andrew J. Gentles, Evan Roberts, Daniel Bilbao-Cortes, Francisco Vega, Jennifer R. Chapman, Ramiro E. Verdun, Izidore S. Lossos

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)237-249.e6
JournalCancer Cell
Volume36
Issue number3
DOIs
StatePublished - Sep 16 2019
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Parvin, S., Ramirez-Labrada, A., Aumann, S., Lu, X. Q., Weich, N., Santiago, G., Cortizas, E. M., Sharabi, E., Zhang, Y., Sanchez-Garcia, I., Gentles, A. J., Roberts, E., Bilbao-Cortes, D., Vega, F., Chapman, J. R., Verdun, R. E., & Lossos, I. S. (2019). LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. Cancer Cell, 36(3), 237-249.e6. https://doi.org/10.1016/j.ccell.2019.07.007