Sphingosine kinases, of which there are two isoforms, catalyze the synthesis of sphingosine 1-phosphate (S1P) from sphingosine. While sphingosine kinase 1 has indisputable tumor-promoting properties, the role of sphingosine kinase 2 in cancer is less clear. We show that sphingosine kinase 2 plays an oncogenic role in acute lymphoblastic leukemia by influencing the expression of the oncogene MYC. Sphingosine kinase 2 protein was over-expressed in leukemic cell lines and patient samples, although there was no change in gene expression. Genetic loss of sphingosine kinase 2 impaired leukemia development in a murine model, while pharmacological inhibition significantly extended survival in mouse xenograft models of human disease. Inhibition or genetic deletion of sphingosine kinase 2 reduced expression of MYC in leukemic cells. This was associated with reduced association of acetylated histone H3 with the MYC gene and lower expression of the Myc proto-oncogene protein (c-Myc) and c-Myc regulated genes. Direct inhibition of c-Myc resulted in the death of acute lymphoblastic leukemia cells, supporting a direct role for c-Myc in the demise of leukemic cells exposed to sphingosine kinase 2 inhibitors. This demonstrates that sphingosine kinase 2 can regulate MYC, which plays an important role in hematological malignancies, and therefore this pathway may prove a useful therapeutic target in this disease. The sphingosine kinase 2 inhibitor, ABC294640, is in clinical trial for solid tumors making the potential translation of this approach feasible.