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.
- Copyright © 2013 by The American Association of Immunologists, Inc.