MLL遺伝子再構成陽性ヒトBリンパ性白血病細胞株におけるバルプロ酸によるアポトーシスの誘導

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  • Valproic acid induces apoptosis in human B-lymphoid leukemia cell lines with MLL rearrangements

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Abstract

Increasing evidence has shown that short chain fatty acids induce differentiation or apoptosis in a variety of tumor cells. Valproic acid (VPA) is one of them and has been widely used as an anti-epileptic drug in clinical scenes. Mixed Lineage Leukemia (MLL) gene is frequently rearranged in infantile leukemias and treatment-related leukemias. The prognosis of leukemias with MLL rearrangements is often poor. In this study we investigated the effect of VPA on the survival of human B-lymphoid leukemia cell lines with MLL rearrangements. When 3 human B-lymphoid leukemia cell lines were cultured with VPA at various concentrations, VPA induced cell death in all the cell lines tested in a dose dependent manner. At the clinically used concentration, VPA effectively killed 2 of 3 cell lines tested, which were resistant to the predonisolone treatment. This fact suggests that VPA induces cell death through a different pathway from that of predonisolone. Morphological analysis of VPA-teated cells demonstrated the shrinkage of the cells and the nuclear chromatin condensation. Agarose gel electrophoresis showed that VPA caused the DNA fragmentation in these cells. Flow cytometric analysis of the cells stained with annexinV revealed that VPA induced the externalization of phosphatidylserine. These findings indicate that VPA induces apoptosis in human B-lymphoid leukemia cell lines tested in this study. VPA can be used as an anti-1eukemic drug without serious adverse effect.

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