Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia
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Naomi E. van der Sligte1, Kim R. Kampen1, Arja ter Elst1, Frank J.G. Scherpen1, Tiny G.J. Meeuwsen-de Boer1, Victor Guryev2, Frank N. van Leeuwen3, Steven M. Kornblau4, Eveline S.J.M. de Bont1
1Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2European Research Institute for The Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
3Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
4Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
Eveline S.J.M. de Bont, e-mail: [email protected]
Keywords: acute lymphoblastic leukemia, cyclic-AMP responsive element binding protein, CREB, targeted therapy
Received: January 28, 2015 Accepted: April 24, 2015 Published: May 06, 2015
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.
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