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

ABSTRACT: Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN). Here we investigated the activity of a potent and selective PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 efficiently antagonized Wnt signaling in human CML CD34⁺ cells, and in combina

SUBMITTER: Agarwal P 

PROVIDER: S-EPMC5324714 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature