Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI

cells, and in combination with the TKI nilotinib (NIL) significantly enhanced inhibition of proliferation and colony-forming potential of CML stem and progenitor cells and reduced their growth in immunodeficient mice in vivo, in comparison with NIL alone. Treatment of transgenic CML mice in vivo with NIL in combination with WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced regeneration of leukemic long-term hematopoietic stem cells in secondary transplant recipients, and enhanced survival of mice after discontinuation of treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced sensitivity to Wnt stimulation, associated with increased expression of the FZD4 receptor. FZD4 knockdown inhibited CML progenitor growth. These results support further investigation of PORCN targeting to inhibit Wnt secretion and signaling and enhance targeting of CML stem cells while sparing their normal counterparts.