Inhibition Of S100A6 Induces Graft Versus Leukemia Effects In MLL/AF4-Positive ALL In Human PBMC-SCID Mice

Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL-AF4-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-a) was reported to contribute to the GVL effect. We reported previously that MLL/AF4-positive ALL shows resistance to TNF-a, which is the main factor in GVL effect, by upregulation of S100A6 expression followed by interference with the p53-caspase 8-caspase 3 pathway in vitro. We examined whether inhibition of S100A6 can induce an effective GVL effect on MLL/AF4-positive ALL in a mouse model. To examine the long-term effects of inhibition of S100A6,MLL/AF4-positive ALL cell lines (SEM) transduced with lentiviral vectors expressing both S100A6 siRNA and luciferase (SEM-Luc-S100A6 siRNA) were produced. SEM-Luc-S100A6 siRNA cells and SEM-Luc-control siRNA cells were injected into groups of five SCID mice (1×10⁷/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8×10⁷ human peripheral blood mononuclear cells (PBMCs). Although there were no significant differences between the serum concentrations of human-TNF-a after injection of human PBMCs of SEM-Luc-S100A6 siRNA injected mice and those of SEM-Luc-control siRNA injected mice (P=0.95), SEM-Luc-S100A6 siRNA-injected mice showed significantly longer survival periods than SEM-Luc-control siRNA-injected mice (P = 0.002). SEM-Luc-S100A6 siRNA-injected mice showed significantly slower tumor growth than those injected with SEM-Luc-control siRNA (P < 0.0001). These results suggested that inhibition of S100A6 may be a promising therapeutic target for MLL/AF4-positive ALL in combination with allo-HSCT because it induce effective GVL effectson MLL/AF4-positive ALL which is resistant to GVL effects.