Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression

Craig Wallington-Beddoe; Jason Powell; Daochen Tong; Stuart Pitson; Kenneth Bradstock; Linda Bendall

doi:10.1158/0008-5472.CAN-13-2732

Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression

Craig Wallington-Beddoe, Jason Powell, Daochen Tong, Stuart Pitson, Kenneth Bradstock, Linda Bendall

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2803-2815
Number of pages	13
Journal	Cancer Research
Volume	74
Issue number	10
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-2732
Publication status	Published - 15 May 2014
Externally published	Yes

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abstract = "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.",

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AU - Powell, Jason

AU - Tong, Daochen

AU - Pitson, Stuart

AU - Bradstock, Kenneth

AU - Bendall, Linda

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Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression

Abstract

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