The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2).
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.
Division of Hematology and Oncology, and 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.
Lalitha
L
Nayak
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.
Hong
H
Shi
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.
G Brandon
GB
Atkins
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.
Zhiyong
Z
Lin
Division of Hematology and Oncology, and.
Alvin H
AH
Schmaier
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.
Mukesh K
MK
Jain
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D054059:Coronary Occlusion / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D019610:Cytoprotection / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011719:Pyrazines / Q000494:pharmacology*; D014914:Whole Blood Coagulation Time
D001897:Boronic Acids; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011719:Pyrazines; D000069286:Bortezomib