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 Citation (Scopus)

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

Fingerprint

Poly(ADP-ribose) Polymerases
Lymphoma, Large B-Cell, Diffuse
T-Cell Lymphoma
Homologous Recombination
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Double-Stranded DNA Breaks
Therapeutic Uses
Ovarian Neoplasms
Breast Neoplasms
Drug Therapy
Synthetic Lethal Mutations
Growth
Poly(ADP-ribose) Polymerase Inhibitors
Neoplasms
Proteins
Therapeutics

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., ... 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

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. / Parvin, Salma; Ramirez-Labrada, Ariel; Aumann, Shlomzion; Lu, Xiao Qing; Weich, Natalia; Santiago, Gabriel; Cortizas, Elena M.; Sharabi, Eden; Zhang, Yu; Sanchez-Garcia, Isidro; Gentles, Andrew J.; Roberts, Evan; Bilbao-Cortes, Daniel; Vega, Francisco; Chapman, Jennifer R.; Verdun, Ramiro E.; Lossos, Izidore S.

In: Cancer Cell, Vol. 36, No. 3, 16.09.2019, p. 237-249.e6.

Research output: Contribution to journalArticle

Parvin, S, Ramirez-Labrada, A, Aumann, S, Lu, XQ, Weich, N, Santiago, G, Cortizas, EM, Sharabi, E, Zhang, Y, Sanchez-Garcia, I, Gentles, AJ, Roberts, E, Bilbao-Cortes, D, Vega, F, Chapman, JR, Verdun, RE & Lossos, IS 2019, 'LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL', Cancer Cell, vol. 36, no. 3, pp. 237-249.e6. https://doi.org/10.1016/j.ccell.2019.07.007
Parvin S, Ramirez-Labrada A, Aumann S, Lu XQ, Weich N, Santiago G et al. LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. Cancer Cell. 2019 Sep 16;36(3):237-249.e6. https://doi.org/10.1016/j.ccell.2019.07.007
Parvin, Salma ; Ramirez-Labrada, Ariel ; Aumann, Shlomzion ; Lu, Xiao Qing ; Weich, Natalia ; Santiago, Gabriel ; Cortizas, Elena M. ; Sharabi, Eden ; Zhang, Yu ; Sanchez-Garcia, Isidro ; Gentles, Andrew J. ; Roberts, Evan ; Bilbao-Cortes, Daniel ; Vega, Francisco ; Chapman, Jennifer R. ; Verdun, Ramiro E. ; Lossos, Izidore S. / LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. In: Cancer Cell. 2019 ; Vol. 36, No. 3. pp. 237-249.e6.
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