3158 - SCD Takes Leukemia to the CNS

Abstract

Background: In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern with no specific therapy. Prophylactic CNS-directed intrathecal chemotherapy or irradiation are required for relapse-free survival but imply long term toxicity. Therefore, mechanisms mediating leukemia-cell entry and survival into the CNS need to be understood to develop alternative CNS-directed treatment strategies. Previous studies showed an increased expression of Steroyl CoA desaturase (SCD) in BCP-ALL cells isolated from cerebrospinal fluid (CSF) of patients at CNS relapse. Aim: Investigate if SCD have a role in leukemia trafficking, homing and survival into the CNS in order to design new diagnostic and reduced toxicity- treatments to prevent relapse. Methods:Microarray profiling of cells isolated from CNS and BM of xeno-transplanted mice was performed.Human BCP-ALL cell line 018z was transduced to knock-down (KD) or overexpress human SCD. In vivo, SCD KD and overexpressing cells were transplanted in NSG mice who were sacrificed upon the first symptoms of CNS involvement. BM, spleen and meninges were collected and analyzed to check human engraftment by FACS. In Competition assays, SCD overexpressing and WT cells were transplanted in the same mouse in a 1:1 ratio. Results: Microarray profiling of cells collected from BM and meninges of leukemic mice revealed up-regulation of the genes belonging to the signaling pathway of sterol regulatory element binding proteins (SREBPs) in ALL cells that had entered the CNS, includingSCD. In vitro, SCD-KD 018z cells showed reduced proliferation than WT while SCD overexpression did not alter proliferation.Mice transplanted with SCD KD cells showed a general lower infiltration whereas SCD overexpression led to a faster onset of CNS disease.Competition assays showed that in the CNS the balance was skewed towards engraftment of SCD overexpressing cells over WT. Conclusion: SCD has a role in homing and survival of leukemic cells in the CNS.The research can lead to innovative therapies that will minimize the need for intensive chemotherapy in the CNS.