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

doi:10.1016/j.ccell.2019.07.007

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 journal › Article › peer-review

57 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 language	English
Pages (from-to)	237-249.e6
Journal	Cancer Cell
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2019.07.007
State	Published - 16 Sep 2019
Externally published	Yes

Keywords

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

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10.1016/j.ccell.2019.07.007

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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

@article{3f9674eb2a07497a82c3dcb88352c283,

title = "LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL",

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",

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

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = sep,

day = "16",

doi = "10.1016/j.ccell.2019.07.007",

language = "English",

volume = "36",

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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

TY - JOUR

T1 - LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

AU - Parvin, Salma

AU - Ramirez-Labrada, Ariel

AU - Aumann, Shlomzion

AU - Lu, Xiao Qing

AU - Weich, Natalia

AU - Santiago, Gabriel

AU - Cortizas, Elena M.

AU - Sharabi, Eden

AU - Zhang, Yu

AU - Sanchez-Garcia, Isidro

AU - Gentles, Andrew J.

AU - Roberts, Evan

AU - Bilbao-Cortes, Daniel

AU - Vega, Francisco

AU - Chapman, Jennifer R.

AU - Verdun, Ramiro E.

AU - Lossos, Izidore S.

PY - 2019/9/16

Y1 - 2019/9/16

N2 - 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.

AB - 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.

KW - 53BP1

KW - BRCA1

KW - DNA damage

KW - LMO2

KW - PARP

KW - R-CHOP

KW - acute lymphoblastic leukemia

KW - diffuse large B cell lymphoma (DLBCL)

KW - homologous recombination

KW - olaparib

KW - synthetic lethality

UR - http://www.scopus.com/inward/record.url?scp=85071900409&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.07.007

DO - 10.1016/j.ccell.2019.07.007

M3 - Article

C2 - 31447348

AN - SCOPUS:85071900409

SN - 1535-6108

VL - 36

SP - 237-249.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

Abstract

Keywords

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