Brief Report THROMBOSIS AND HEMOSTASIS The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2)

Cancer is associated with a high risk of thrombosis. Among hematologic malignancies, multiple myeloma (MM) has an especially high rate of both arterial and venous thrombotic events (VTEs). Further, patients treated with the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide experience a substantially elevated VTE risk (15% to 30%). In sharp contrast, MM patients receiving proteasome inhibitor bortezomib (BZ) have a VTE risk that is less than 4%. BZ treatment in hypertensive rat models consistently decreases arterial thrombosis. Although in vitro and ex vivo studies show that BZ inhibits platelet aggregation, the magnitude of this effect is not sufficient for explaining the profound decrease in VTEs noted with BZ. Consequently, alternative mechanisms are likely operative and account for the antithrombotic effects of BZ. Kruppel-like factor 2 (KLF2) is amember of the zincfinger family of transcription factors, which are highly expressed in endothelial and hematopoietic cells. Studies in our laboratory identified KLF2 as a key regulator of endothelial and myeloid inflammation with favorable antithrombotic properties. Further, studies conducted by us and others reveal that BZ induces KLF2 messenger RNA (mRNA) in endothelial and hematopoietic cells. Because endothelial and hematopoietic cells are centrally involved in thrombotic events, we hypothesized that the antithrombotic effect noted with BZ may be KLF2 dependent.