Crosstalk between BCR-ABL and protease-activated receptor 1 (PAR1) suggests a novel target in chronic myeloid leukemia.

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which generates the oncogene BCR-ABL1. Protease-activated receptor 1 (PAR1) is involved in tumor progression and angiogenesis. We have previously reported that PAR1 expression is elevated in human leukemias that display a more aggressive clinical behavior, including the blast crisis of CML. In this study, we analyzed the crosstalk between the oncoprotein BCR-ABL and PAR1 in CML. Leukemic cell lines transfected with the BCR-ABL1 oncogene showed significantly higher expression levels of PAR1 compared with that of wild-type counterparts. This phenomenon was reversed by treatment with tyrosine kinase inhibitors (TKIs). Conversely, treatment with the PAR1 antagonist SCH79797 inhibited BCR-ABL expression. The PAR1 antagonist induced apoptosis in a dose- and time-dependent manner. Higher vascular endothelial growth factor (VEGF) levels were observed in cells transfected with BCR-ABL1 than in their wild-type counterparts. VEGF expression was strongly inhibited after treatment with either TKIs or the PAR1 antagonist. Finally, we evaluated PAR1 expression in CML patients who were either in the blast or chronic phases and had either received TKI treatment or no treatment. A significant decrease in PAR1 expression was observed in treatment-responsive patients, as opposed to a significant increase in PAR1 expression levels in treatment-resistant patients. Patients classified as high risk according to the Sokal index showed higher PAR1 expression levels. Our results demonstrate the crosstalk between BCR-ABL and PAR1. These data may offer important insight into the development of new therapeutic strategies for CML.

• Authors: Camilla de S Borges, Aline F Ferreira, Vitor H Almeida, Fausto G Gomes, Maria Gabriela Berzoti-Coelho, Maira da Costa Cacemiro, Natalia S Nunes, Lorena L Figueiredo-Pontes, Belinda P Simões, Fabíola A Castro, Robson Q Monteiro
• Journal: Experimental hematology (Exp Hematol) Vol. 66 Pg. 50-62 (10 2018) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 30076949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• BCR-ABL1 fusion protein, human
• Chromones
• Flavonoids
• Morpholines
• N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Quinazolines
• Receptor, PAR-1
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Fusion Proteins, bcr-abl
• nilotinib
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Case-Control Studies
• Cell Line, Tumor
• Chromones (pharmacology)
• Disease Progression
• Dose-Response Relationship, Drug
• Female
• Flavonoids (pharmacology)
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Gene Expression Regulation, Leukemic
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Male
• Middle Aged
• Morpholines (pharmacology)
• Myeloid Cells (drug effects, metabolism, pathology)
• Philadelphia Chromosome
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Quinazolines (pharmacology)
• Receptor, PAR-1 (genetics, metabolism)
• Signal Transduction
• Treatment Outcome
• Vascular Endothelial Growth Factor A (genetics, metabolism)