Sphingosine Kinase 2 Promotes Acute Lymphoblastic Leukemia by Enhancing MYC Expression

被引：66

作者：

Wallington-Beddoe, Craig T. ^{[1
]}

Powell, Jason A. ^{[3
]}

Tong, Daochen ^{[1
]}

Pitson, Stuart M. ^{[3
]}

Bradstock, Kenneth F. ^{[2
]}

Bendall, Linda J. ^{[1
]}

机构：

[1] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Westmead, NSW 2145, Australia

[2] Westmead Hosp, Dept Hematol, Westmead, NSW 2145, Australia

[3] Univ South Australia & SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia

来源：

CANCER RESEARCH | 2014年 / 74卷 / 10期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

IMATINIB-INDUCED APOPTOSIS; NF-KAPPA-B; MYELOID-LEUKEMIA; CELL-PROLIFERATION; RAD001; EVEROLIMUS; 1-PHOSPHATE; INHIBITORS; PROTEIN; INVOLVEMENT; PROGRESSION;

D O I：

10.1158/0008-5472.CAN-13-2732

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Sphingosine kinase 2 (SK2) may have utility as a prognostic marker in inflammatory diseases such as cancer in which it has been rationalized as a candidate therapeutic target. Here, we show that SK2 has an oncogenic role in acute lymphoblastic leukemia (ALL) by influencing expression of MYC. Genetic ablation of SK2 impaired leukemia development in a mouse model of ALL and pharmacologic inhibition extended survival in mouse xenograft models of human disease. SK2 attenuation in both the settings reduced MYC expression in leukemic cells, with reduced levels of acetylated histone H3 within the MYC gene associated with reduced levels of MYC protein and expression of MYC-regulated genes. Our results demonstrated that SK2 regulates MYC, which has a pivotal role in hematologic malignancies, providing a preclinical proof of concept for this pathway as a broad-based therapeutic target in this setting. Cancer Res; 74(10); 2803-15. (C) 2014 AACR.

引用

页码：2803 / 2815

页数：13

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