OSU-2S: a novel non-immunosuppressive FTY720 derivative mediates potent cytotoxic activity through PKC dependent phosphorylation of tumor suppressor SHP1 and down modulation of Tcl1 oncogene in chronic lymphocytic leukemia (P2120)

Abstract We have recently demonstrated cytotoxic activity of FTY720, a sphingosine analogue, against several B cell malignancies including chronic lymphocytic leukemia (CLL).To overcome the limitations associated with immunosuppressive properties of FTY720, we have developed OSU-2S, a synthetic FTY720 derivative with cytotoxic potency and negated immunosuppressive property. Treatment of primary CLL cells with OSU-2S resulted in potent cytotoxicity associated with PKC mediated phosphorylation of Serine591 (S591) of SHP1 and its nuclear translocation consistent with a potential role for S591 phosphorylation. Concentrations of bisindolylmaleimide that inhibited PKC and thus SHP1S591 phosphorylation abrogated OSU-2S mediated cytotoxicity in CLL cells. Gene expression profiling (GEP) revealed OSU-2S mediated down regulation of TCL1A. Consistent with this OSU-2S induced down regulation of TCL1A at mRNA and protein levels in primary CLL cells. The therapeutic efficacy of OSU-2S was demonstrated in Eµ-Tcl1 transgenic CLL mouse model and SCID-Raji xenograft models with significant reduction in leukemic B cells. Further, administration of OSU-2S immunoliposome targeting receptor tyrosine kinase-like orphan receptor (ROR1) expressed in lymphoid malignancies including CLL in Eμ-human ROR1 transgenic mice resulted in selective depletion of ROR1 positive B cells. In summary, we have identified OSU-2S as a modulator of tumor suppressor and oncogene targets in CLL resulting in potent cytotoxicity.