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Pre-clinical Studies

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 × 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 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.

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Correspondence to H Tamai.

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HT designed and conducted and performed the research, and wrote the paper. KM, HY, KD, TS and KI partially conducted the research.

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Tamai, H., Miyake, K., Yamaguchi, H. et al. Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human PBMC-SCID mice. Bone Marrow Transplant 49, 699–703 (2014). https://doi.org/10.1038/bmt.2014.18

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