CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells.

CREB-binding protein (CBP) and p300 are highly homologous transcriptional coactivators with unique, non-redundant roles that bind a wide array of proteins, including catenins-β and γ. ICG-001 is a small-molecule inhibitor that specifically inhibits the CBP/catenin interaction. Importantly, ICG-001 does not inhibit the p300/catenin interaction. We demonstrate that specifically inhibiting the ...
interaction between CBP and catenin with ICG-001 results in the differentiation of quiescent drug-resistant chronic myelogenous leukemia-initiating cells (CML LICs), thereby sensitizing them to BCR-ABL tyrosine kinase inhibitors, for example, Imatinib. Using ICG-001 in a NOD/SCID/IL2Rγ(-/-) mouse model of engrafted human chronic myelogenous leukemia, we now demonstrate the complete elimination of engrafted leukemia after only one course of combined chemotherapy. Combination-treated animals live as long as their non-engrafted littermates. Results from these studies demonstrate that specifically antagonizing the CBP/catenin interaction with ICG-001 can eliminate drug-resistant CML LICs without deleterious effects to the normal endogenous hematopoietic stem cell population.
Mesh Terms:
Animals, Bridged Bicyclo Compounds, Heterocyclic, CREB-Binding Protein, Catenins, Cell Line, Tumor, Drug Resistance, Neoplasm, E1A-Associated p300 Protein, Female, Fusion Proteins, bcr-abl, Humans, Immunoblotting, Interleukin Receptor Common gamma Subunit, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplastic Stem Cells, Protein Binding, Pyrimidinones, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays
Oncogene
Date: Jul. 14, 2016
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