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

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL.

Author information

1
Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA.
2
Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
3
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
4
Departments of Medicine, and Biomedical Data Science, Stanford University, Stanford, CA, USA.
5
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
6
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Department of Pathology and Laboratory Medicine, Division of Hematopathology, University of Miami, Miami, FL, USA.
7
Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Geriatric Research, Education, and Clinical Center, Miami VA Healthcare System, Miami, FL, USA. Electronic address: rverdun@med.miami.edu.
8
Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA. Electronic address: ilossos@med.miami.edu.

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

PMID:
31447348
PMCID:
PMC6752209
[Available on 2020-09-16]
DOI:
10.1016/j.ccell.2019.07.007

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