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The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2).
Pubmed ID: 24771858
Pubmed Central ID: PMC4055929
Journal: Blood
Publication Date: June 12, 2014
Affiliation: Harrington Heart and Vascular Institute, Case Cardiovascular Research Institute, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH.
MeSH Terms: Humans, Cells, Cultured, Animals, Mice, Human Umbilical Vein Endothelial Cells, Mice, Knockout, Kruppel-Like Transcription Factors, Mice, Inbred C57BL, Carotid Artery Thrombosis, Boronic Acids, Coronary Occlusion, Cytoprotection, Pyrazines, Whole Blood Coagulation Time, Bortezomib
Grants: R21 HL112666, HL086548, HL097593, R01 HL097593, R01 HL119195, HL112666-02, HL112486, HL052279-18, HL087595, HL117759, HL119195, R01 HL075427, R01 HL117759, R01 HL123098, R01 HL112486, R01 HL086548, R00 HL087595, K99 HL087595
Authors: Schmaier AH, Nayak L, Shi H, Atkins GB, Jain MK, Lin Z
Cite As: Nayak L, Shi H, Atkins GB, Lin Z, Schmaier AH, Jain MK. The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2). Blood 2014 Jun 12;123(24):3828-31. Epub 2014 Apr 25.
Studies:
Abstract
Multiple myeloma confers a high risk for vascular thrombosis, a risk that is increased by treatment with immunomodulatory agents. Strikingly, inclusion of the proteasome inhibitor bortezomib reduces thrombotic risk, yet the molecular basis for this observation remains unknown. Here, we show that bortezomib prolongs thrombosis times in the carotid artery photochemical injury assay in normal mice. Cell-based studies show that bortezomib increases expression of the transcription factor Kruppel-like factor 2 (KLF2) in multiple cell types. Global postnatal overexpression of KLF2 (GL-K2-TG) increased time to thrombosis, and global postnatal deletion of KLF2 (GL-K2-KO) conferred an antiparallel effect. Finally, studies in GL-K2-KO mice showed that the thromboprotective effect of bortezomib is KLF2 dependent. These findings identify a transcriptional basis for the antithrombotic effects of bortezomib.