Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells

• Published in: Leukemia Vol. 30; no. 12; pp. 2302 - 2311
• Main Authors: Mitton, B, Chae, H -D, Hsu, K, Dutta, R, Aldana-Masangkay, G, Ferrari, R, Davis, K, Tiu, B C, Kaul, A, Lacayo, N, Dahl, G, Xie, F, Li, B X, Breese, M R, Landaw, E M, Nolan, G, Pellegrini, M, Romanov, S, Xiao, X, Sakamoto, K M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2016; Nature Publishing Group
• Subjects: 13/31; 38/39; 42/109; 59/5; 631/67; 631/67/1990; 631/67/1990/283/1897; 692/699/67/1059/602; 96/100; Acute myeloid leukemia; Animal tissues; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biocompatibility; Cancer Research; Cell Cycle Checkpoints - drug effects; Cell growth; Cell Line, Tumor; Cell survival; Chemotherapy; CREB-Binding Protein - antagonists & inhibitors; CREB-Binding Protein - metabolism; Critical Care Medicine; Cyclic adenylic acid; Cyclic AMP response element-binding protein; Cytometry; Gene expression; Genetic aspects; Hematology; Hematopoietic stem cells; Heterografts; Humans; In vivo methods and tests; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Medical prognosis; Medicine; Medicine & Public Health; Mice; Oncology; original-article; Patients; Pediatrics; Peptide Fragments - metabolism; Physiological aspects; Properties; Protein Binding - drug effects; Proteins; Sialoglycoproteins - metabolism; Stem cells; Survival; Survival Rate; Therapeutic targets; Toxicity; Transcription factors; Transplantation; Los Angeles California; United States > US; California
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.139

The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro . In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP–CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP–CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.