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G protein-coupled receptor 56  ( GPR56 ) is highly expressed in acute myeloid leukemia (AML) cells with high EVI1 expression (EVI1 high  AML). Because  GPR56  is a transcriptional target of EVI1 and silencing of  GPR56  expression induces apoptosis, we developed a novel drug to suppress  GPR56  expression in EVI1 high  AML cells. For this purpose, we generated pyrrole-imidazole (PI) polyamides specific to  GPR56  (PIP/56-1 or PIP/56-2) as nuclease-resistant novel compounds that interfere with the binding of EVI1 to the  GPR56  promoter in a sequence-specific manner. Treatment of EVI1 high  AML cell lines (UCSD/AML1 and Kasumi-3) with PIP/56-1 or PIP/56-2 effectively suppressed  GPR56  expression by inhibiting binding of EVI1 to its promoter, leading to suppression of cell growth with increased rates of apoptosis. Moreover, intravenous administration of PIP/56-1 into immunodeficient Balb/c-RJ mice subcutaneously transplanted with UCSD/AML1 cells significantly inhibited tumor growth and extended survival. Furthermore, organ infiltration by leukemia cells in immunodeficient Balb/c-RJ mice, which were intravenously transplanted using UCSD/AML1 cells, was successfully inhibited by PIP/56-1 treatment with no apparent effects on murine hematopoietic cells. In addition, PIP treatment did not inhibit colony formation of human CD34 +  progenitor cells. Thus, PI polyamide targeting of  GPR56  using our compound is promising, useful, and safe for the treatment of EVI1 high  AML.

Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expression