LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

被引：60

作者：

Parvin, Salma ^{[1
]}

Ramirez-Labrada, Ariel ^{[1
,2
,10
]}

Aumann, Shlomzion ^{[1
,2
]}

Lu, XiaoQing ^{[1
,2
]}

Weich, Natalia ^{[1
,2
]}

Santiago, Gabriel ^{[1
]}

Cortizas, Elena M. ^{[1
]}

Sharabi, Eden ^{[1
]}

Zhang, Yu ^{[1
]}

Sanchez-Garcia, Isidro ^{[3
,4
]}

Gentles, Andrew J. ^{[5
,6
]}

Roberts, Evan ^{[2
]}

Bilbao-Cortes, Daniel ^{[2
]}

Vega, Francisco ^{[2
,7
]}

Chapman, Jennifer R. ^{[2
,7
]}

Verdun, Ramiro E. ^{[1
,2
,8
]}

Lossos, Izidore S. ^{[1
,2
,9
]}

机构：

[1] Univ Miami, Miller Sch Med, Dept Med, Div Hematol, 1600 NW 10th Ave,1475 NW 12th Ave D8-4, Miami, FL 33136 USA

[2] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[3] Univ Salamanca, Expt Therapeut & Translat Oncol Program, Inst Biol Mol & Celular Canc, CSIC, Salamanca, Spain

[4] Inst Biomed Res Salamanca IBSAL, Salamanca, Spain

[5] Stanford Univ, Dept Med, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA

[7] Univ Miami, Dept Pathol & Lab Med, Div Hematopathol, Miami, FL 33136 USA

[8] Miami VA Healthcare Syst, Geriatr Res Educ & Clin Ctr, Miami, FL 33125 USA

[9] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA

[10] Biomed Res Ctr Aragon CIBA, Fdn Inst Invest Sanit Aragon IIS Aragon, Zaragoza 50009, Spain

来源：

CANCER CELL | 2019年 / 36卷 / 03期

关键词：

STRAND BREAK REPAIR; DNA-DAMAGE; CHOP CHEMOTHERAPY; RITUXIMAB-CHOP; B-CELLS; 53BP1; EXPRESSION; RECOMBINATION; RESECTION; BRCA;

D O I：

10.1016/j.ccell.2019.07.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：237 / +

页数：19

共 67 条

[1] Detection of LIM domain only 2 (LMO2) in normal human tissues and haematopoietic and non-haematopoietic tumours using a newly developed rabbit monoclonal antibody [J].