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

Autor: Mitton B; Department of Pediatrics, Stanford University, Stanford, CA, USA., Chae HD; Department of Pediatrics, Stanford University, Stanford, CA, USA., Hsu K; Department of Pediatrics, Stanford University, Stanford, CA, USA., Dutta R; Department of Pediatrics, Stanford University, Stanford, CA, USA., Aldana-Masangkay G; Department of Pediatrics, Stanford University, Stanford, CA, USA., Ferrari R; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA., Davis K; Department of Pediatrics, Stanford University, Stanford, CA, USA., Tiu BC; Department of Pediatrics, Stanford University, Stanford, CA, USA., Kaul A; Department of Pediatrics, Stanford University, Stanford, CA, USA., Lacayo N; Department of Pediatrics, Stanford University, Stanford, CA, USA., Dahl G; Department of Pediatrics, Stanford University, Stanford, CA, USA., Xie F; Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA., Li BX; Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA., Breese MR; Department of Pediatrics, Stanford University, Stanford, CA, USA., Landaw EM; Department of Biomathematics, University of California, Los Angeles, Los Angeles, CA, USA., Nolan G; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA., Pellegrini M; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA., Romanov S; Nanosyn, Inc., Santa Clara, CA, USA., Xiao X; Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA., Sakamoto KM; Department of Pediatrics, Stanford University, Stanford, CA, USA.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2016 Dec; Vol. 30 (12), pp. 2302-2311. Date of Electronic Publication: 2016 May 23.
DOI: 10.1038/leu.2016.139
Abstrakt: 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.
Competing Interests: G. N. has personal financial interest in the company DVS Sciences, the manufacturers that produced some of the reagents and instrumentation used in this manuscript.
Databáze: MEDLINE
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