title: Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mitton
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: H-D
authors.initials: HD
authors.lastname: Chae
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dutta
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Aldana-Masangkay
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Tiu
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kaul
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lacayo
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Dahl
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA.
authors.forename: F
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA.
authors.forename: B X
authors.initials: BX
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Breese
authors.affiliation: Department of Biomathematics, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Landaw
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Nolan
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: M
authors.identifier: 0000-0001-9355-9564
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Nanosyn, Inc., Santa Clara, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Romanov
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, OR, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012795:Sialoglycoproteins / Q000378:metabolism; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D012795:Sialoglycoproteins; C571744:bone sialoprotein (35-62), human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human