Inhibition of proteasome restores bortesomib-induced thrombocytopenia

 

Bortesomib is a effective proteasome inhibitor used in the therapy against multiple myeloma, however, it often induces thrombocytopenia, a decrease of platelet count, within a short term of therapy initiation. This effect can be recovered after cessation of bortezomib treatment. Due to the unknown mechanism of how bortezomib affects thrombopoiesis, several studies aim to find out the role of proteasome in platelet formation. Shi et al. reported clinical proteasome inhibitor enable to block proplatelet formation by megakaryocytes in human and mouse model. The article was published in The Journal of Clinical Investigation.

 

Researchers found the systemic or platelet-specific lacking of PSMC1 , a subunit of the 26S proteasome, caused failure of proplatelet production by megakaryocytes or thrombocytopenia-induced death, respectively. Mechanically, they found the failure of proplatelet production in PSMC1 deficient megakaryocytes is caused by aberrant increase of RhoA, a small GTPase. The formation of proplatelet can be restored by either inhibiting RhoA or its downstream target, Rho-associated protein kinase (ROCK). A ROCK inhibitor, fasudil, restored thrombopoiesis in mice with thrombocytopenic induced by the suppression of proteasome activity resulted from tamoxifen usage. The findings revealed the important role of RhoA and ROCK signaling in mediating proplatelet formation by megakaryocutes, and made them potential targets for treatment of bortezomib-induced thrombocytopenia in multiple myeloma patients.

 

Reference:
J Clin Invest. 2014 Sep;124(9):3757-66. 

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Related Targets

Proteasome ROCK Autophagy