Sphingosine Kinase 2 Promotes Acute Lymphoblastic Leukemia by Enhancing MYC Expression

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. Cancer Res; 74(10); 2803-15. Ó2014 AACR.

Recent advances in the development of sphingosine kinase inhibitors

“…Despite the off-targets, ABC294640 was found to sensitise cancer cells to chemotherapy [50,[114][115][116][117][118], Bcl-2 inhibitors [37], the Bcr-Abl inhibitor Imatinib and the proteasome inhibitor Bortezomib [36]. ABC294640 was found to reduce pro-proliferative signalling through the Akt and MAPK pathways via reduction in S1P receptor signalling.…”

“…In addition to a large number of studies demonstrating the anti-cancer effects of SK1 inhibitors [25][26][27][28][29][30][31][32] (reviewed in [33,34]), siRNA knockdown of SK1 has also been shown to induce cell death and confer sensitivity to chemo-or radiation therapy of cancer lines (reviewed in [33][34][35]). The potential of SK2 as an oncology target has emerged more recently, with several SK2-selective inhibitors showing anti-cancer effects, with one progressing to clinical trials (see Section 4.1), and siRNA knockdown studies also showing the efficacy of targeting this isoform in some cancers, including acute lymphocytic leukaemia [36], multiple myeloma [37], glioblastoma [38] and kidney and breast cancer [39]. Notably, SK1 −/− or SK2 −/− mice have also shown reduced tumour growth in a number of in vivo cancer models [25][26][27][28][29][30][31][32]36,40].…”

“…The potential of SK2 as an oncology target has emerged more recently, with several SK2-selective inhibitors showing anti-cancer effects, with one progressing to clinical trials (see Section 4.1), and siRNA knockdown studies also showing the efficacy of targeting this isoform in some cancers, including acute lymphocytic leukaemia [36], multiple myeloma [37], glioblastoma [38] and kidney and breast cancer [39]. Notably, SK1 −/− or SK2 −/− mice have also shown reduced tumour growth in a number of in vivo cancer models [25][26][27][28][29][30][31][32]36,40]. These studies have rendered both SKs as attractive targets for drug development [34,35].…”

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

“…Moreover, SK2 inhibitor genetic signatures are correlated to a publicly available gene expression dataset derived from paediatric T-and B-ALL patients (Wallington-Beddoe et al, 2014). In addition, SK2 has been implicated in maintaining cancer cell survival in various tumours.…”

“…In addition, SK2 has been implicated in maintaining cancer cell survival in various tumours. Thus, siRNA knockdown of SK2 expression has been shown to induce autophagic death of several different cancer cell lines (Gao & Smith, 2011) and S1P, formed by SK2, can inhibit HDAC1/2 to induce epigenetic regulation of genes involved in B-ALL, such as c-Myc (Hait et al, 2009;Wallington-Beddoe et al, 2014). Significantly, the death of T-ALL cells induced by ROMe is reversed by inhibitors of autophagy but not apoptosis (Evangelisti et al, 2014).…”