title: Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human PBMC-SCID mice.
abstract: Mixed-lineage leukemia (MLL)/AF4-positive ALL is associated with a poor prognosis even after allogeneic hematopoietic SCT (allo-HSCT). We reported previously that MLL/AF4-positive ALL shows resistance to TNF-α, which is the main factor in the 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. 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 × 10(7)/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8 × 10(7) human PBMCs. 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.
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tamai
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Dan
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Inokuchi
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D020544:Graft vs Leukemia Effect / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016513:Mice, SCID; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000235:genetics*; D035602:Transcriptional Elongation Factors; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; D035602:Transcriptional Elongation Factors; D014409:Tumor Necrosis Factor-alpha; C055351:S100A6 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D008156:Luciferases