EphB1 Suppression in Acute Myelogenous Leukemia: Regulating the DNA Damage Control System.

Abstract

UNLABELLED:

Loss of ephrin receptor (EphB1) expression may associate with aggressive cancer phenotypes; however, the mechanism of action remains unclear. To gain detailed insight into EphB1 function in acute myelogenous leukemia (AML), comprehensive analysis of EphB1 transcriptional regulation was conducted. In AML cells, EphB1 transcript was inversely correlated with EphB1 promoter methylation. The presence of EphB1 allowed EfnB1 ligand-mediated p53 DNA binding, leading to restoration of the DNA damage response (DDR) cascade by the activation of ATR, Chk1, p53, p21, p38, CDK1(tyr15), and Bax, and downregulation of HSP27 and Bcl2. Comparatively, reintroduction of EphB1 expression in EphB1-methylated AML cells enhanced the same cascade of ATR, Chk1, p21, and CDK1(tyr15), which consequently enforced programmed cell death. Interestingly, in pediatric AML samples, EphB1 peptide phosphorylation and mRNA expression were actively suppressed as compared with normal bone marrow, and a significant percentage of the primary AML specimens had EphB1 promoter hypermethylation. Finally, EphB1 repression associated with a poor overall survival in pediatric AML. Combined, the contribution of EphB1 to the DDR system reveals a tumor-suppressor function for EphB1 in pediatric AML.

IMPLICATIONS:

The tumor-suppressor function of EphB1 is clinically relevant across many malignancies, suggesting that EphB1 is an important regulator of common cancer cell transforming pathways.

• Authors: K R Kampen, F J G Scherpen, G Garcia-Manero, H Yang, G J L Kaspers, J Cloos, C M Zwaan, M M van den Heuvel-Eibrink, S M Kornblau, E S J M De Bont
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 6 Pg. 982-92 (Jun 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25944917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• EPHB2 protein, human
• Receptor, EphA1
• Receptor, EphB2

Topics

• Apoptosis
• Bone Marrow
• Cell Line, Tumor
• Child
• DNA Damage
• DNA Methylation
• DNA Repair
• Down-Regulation
• G2 Phase Cell Cycle Checkpoints
• Humans
• Leukemia, Myeloid, Acute (metabolism, pathology)
• Promoter Regions, Genetic
• Receptor, EphA1 (metabolism)
• Receptor, EphB2 (metabolism)