title: Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL) relapse remains a leading cause of cancer related death in children, therefore, new therapeutic options are needed. Recently, we showed that a peptide derived from Cyclic-AMP Responsive Element Binding Protein (CREB) was highly phosphorylated in pediatric leukemias. In this study, we determined CREB phosphorylation and mRNA levels showing that CREB expression was significantly higher in ALL compared to normal bone marrow (phosphorylation: P < 0.0001, mRNA: P = 0.004). High CREB and phospho-CREB expression was correlated with a lower median overall survival in a cohort of 140 adult ALL patients. ShRNA mediated knockdown of CREB in ALL cell lines blocked leukemic cell growth by inducing cell cycle arrest and apoptosis. Gene expression array analysis showed downregulation of CREB target genes regulating cell proliferation and glucose metabolism and upregulation of apoptosis inducing genes. Similar to CREB knockdown, the CREB inhibitor KG-501 decreased leukemic cell viability and induced apoptosis in ALL cell lines, as well as primary T-ALL samples, with cases showing high phospho-CREB levels being more sensitive than those with lower phospho-CREB levels. Together, these in vitro findings support an important role for CREB in the survival of ALL cells and identify this transcription factor as a potential target for treatment.
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Naomi E
authors.initials: NE
authors.lastname: van der Sligte
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Kim R
authors.initials: KR
authors.lastname: Kampen
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Arja
authors.initials: A
authors.lastname: ter Elst
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Frank J G
authors.initials: FJ
authors.lastname: Scherpen
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Tiny G J
authors.initials: TG
authors.lastname: Meeuwsen-de Boer
authors.affiliation: European Research Institute for The Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D049691:History, Medieval; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D008875:Middle Aged; D009284:Naphthols / Q000494:pharmacology; D010755:Organophosphates / Q000494:pharmacology; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009284:Naphthols; D010755:Organophosphates; C495860:naphthol AS-E phosphate
keywords: CREB; acute lymphoblastic leukemia; cyclic-AMP responsive element binding protein; targeted therapy