Stearoyl-CoA Desaturase (SCD) Promotes Leukemic Metastasis in the Central Nervous System

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern, with poor-prognosis associated. The current therapeutic approach is to treat all leukemia with prophylactic intrathecal chemotherapy which linked with significant neurotoxicity. Lack of mechanistic understanding of CNS leukemia has delayed the development of more targeted, less toxic therapeutic strategies. Metabolic reprogramming is a hallmark of cancer but little is known about how cancer cells reprogram their metabolism when migrating from one compartment to another in metastasis. We, therefore, studied the metabolic adaptation of ALL cells to the microenvironments of the bone marrow and of the CNS. In an in vivo model, leukemic cell lines were injected to mice and then collected from the CNS and peripheral systemic engraftment sites. Gene expression assessment showed an enhanced fatty-acid synthesis signature in CNS leukemia, emphasizing a key role for Stearoyl-CoA desaturase (SCD). Following this lead, mice were transplanted with SCD-overexpressing cells. This demonstrated that increased SCD expression granted leukemic cells an advantage for CNS engraftment. Reciprocally, either genetic ablation or pharmacological inhibition of SCD decreased CNS tumor load. Therefore, we propose that elevated SCD expression is a predictor of CNS relapse in ALL patients. Moreover, this study shows that leukemic cells need to adjust their metabolism in order to adapt to the microenvironmental changes in different compartments, opening a window to target metabolic adaptation as a directed therapeutic strategy.