Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia

被引：66

作者：

Khandanpour, Cyrus ^{[1
,3
]}

Phelan, James D. ^{[4
]}

Vassen, Lothar ^{[1
]}

Schuette, Judith ^{[6
,7
]}

Chen, Riyan ^{[1
]}

Horman, Shane R. ^{[4
]}

Gaudreau, Marie-Claude ^{[1
,2
]}

Krongold, Joseph ^{[1
,8
]}

Zhu, Jinfang ^{[9
]}

Paul, William E. ^{[9
]}

Duehrsen, Ulrich

Goettgens, Bertie ^{[6
,7
]}

Grimes, H. Leighton ^{[4
,5
]}

Moeroey, Tarik ^{[1
,2
,8
]}

机构：

[1] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada

[2] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada

[3] Univ Duisburg Essen, Univ Hosp, Dept Haematol, D-45122 Essen, Germany

[4] Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA

[5] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA

[6] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England

[7] Univ Cambridge, Wellcome Trust, Cambridge Stem Cell Inst, MRC, Cambridge CB2 0XY, England

[8] McGill Univ, Div Expt Med, Montreal, PQ H3A 1A3, Canada

[9] NIAID, Immunol Lab, NIH, Bethesda, MD 20829 USA

来源：

CANCER CELL | 2013年 / 23卷 / 02期

基金：

加拿大健康研究院; 英国生物技术与生命科学研究理事会;

关键词：

FINGER PROTEIN GFI-1; C-MYC; HUMAN NEUTROPENIA; T-ALL; CELL; ACTIVATION; EXPRESSION; NOTCH1; MUTATIONS; CANCER;

D O I：

10.1016/j.ccr.2013.01.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of proapoptotic p53 targets such as Box, Noxa (Pmaip1), and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias.

引用

页码：200 / 214

页数：15

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